Report of the Scientific Working Group meeting on Malaria · iv Report of the Scientific Working...

Report of the Scientific Working Group meeting on Malaria

Geneva, 24–27 March, 2003

TDR/SWG/03

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Report of the Scientific Working Group on Malaria, 2003 • TDR/SWG/03 iii

Executive summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

1. Objectives and expected outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

2. Improved tools and strategies for the treatment of malaria . . . . . . . . . . . . . 7CURRENT STATUS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7Home management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8Malaria in pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8Management of severe malaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8Antimalarial drug research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8Drug resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9Treatment policy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

CHALLENGES AND OPPORTUNITIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9Getting the drugs to the sick patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9Ensuring efficacy of antimalarial drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9Improving implementation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10Managing severe malaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10TDR comparative advantages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10Table 1. SWG prioritization of needed research on improved tools and strategies for the treatment of malaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

3. Improved tools and strategies for the prevention of malaria . . . . . . . . . . . 13CURRENT STATUS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Drug-based interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Vector control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

IMPROVEMENT OF PARTNERSHIP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15Table 2. SWG prioritization of needed research on improved tools and strategies for the prevention of malaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

4. Innovative approaches to the control and prevention of malaria . . . . . . . . 17CURRENT STRATEGIES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17GAPS AND OPPORTUNITIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Cross-cutting approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18Parasite-based interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19Pathogenesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Vector-based interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Table 3. SWG prioritization of needed research on innovative approaches to malaria control and prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Contents

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5. Social, economic, behavioural, health systems and policy research for the treatment and prevention of malaria. . . . . . . . . . . . . . . . . . . . . . . . . . . . 23CURRENT STATUS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23RECOMMENDATIONS FOR FUTURE RESEARCH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

Vulnerability and coping strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23Equity: development and application of a common methodology for measuring socioeconomic status and more qualitative descriptors of poverty and equity . . . . . . . 24Gender and malaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24Improving prevention: comparative multi-disciplinary social research evaluating interventions to scale up and target the distribution of ITNs . . . . . . . . . . . . . . . . . . 24Improving treatment: supply-side research on the private sector . . . . . . . . . . . . . . . . 25Health sector reform and control of malaria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25Public–private partnerships: policy and operational research on impact, viability, sustainability and optimal balance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26Policy, economic and social analysis: understanding the process of change in malaria control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26Ethical, legal and social issues of new malaria-related tools . . . . . . . . . . . . . . . . . . . 26Persistence, emergence and resurgence of malaria . . . . . . . . . . . . . . . . . . . . . . . . . 26Table 4. SWG prioritization of needed research in social, economic, behavioural, health systems and policy aspects of the treatment and prevention of malaria . . . . . . 28

6. Capacity and partnership building . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29Clinical investigation and trials capacity building . . . . . . . . . . . . . . . . . . . . . . . . . 29Drug analytical facilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29Operational research, evaluation of interventions and health care systems . . . . . . . . . 29Bioinformatics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29Functional genomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29Product development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29Social sciences. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

Annex 1 AGENDA: Scientific Working Group on Malaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Annex 2 LIST OF PARTICIPANTS: Scientific Working Group on Malaria . . . . . . . . . . . . . . . . . . . . 35

Annex 3 WORKING PAPER: Effective management of childhood malaria at the community level: programme experience to guide the research agenda. . . . . . . . . . . . . . . . . . . . . . . . . 41

Annex 4 WORKING PAPER: Prevention of malaria in pregnancy . . . . . . . . . . . . . . . . . . . . . . . . 49

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Table 1. Current scientific evidence on dosing regimens for intermittent preventive therapy with SP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50Table 2. Comparison of effectiveness of antimalarial drug regimens used for the prevention of malaria in pregnant women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52Table 3. Possible regimens for antimalarial drugs used for treatment and prophylaxis of malaria in pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53Table 4. Studies of insecticide-treated bednets used in pregnancy . . . . . . . . . . . . . . . 55

Annex 5 WORKING PAPER: New and improved antimalarial drugs . . . . . . . . . . . . . . . . . . . . . . . 61

Annex 6 WORKING PAPER: Insecticide-treated nets – implementation strategies . . . . . . . . . . . . 67

Annex 7 WORKING PAPER: Improving and scaling up vector control, the impact of insecticide resistance and possible means of resistance management . . . . . . . . . . . . . . . . . . . . . 71

Annex 8 WORKING PAPER: Strategies for scaling up intermittent preventive treatment for malaria and anaemia in pregnant women and in children . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

Annex 9 WORKING PAPER: Novel molecular methods for surveillance of resistance to antimalarial drugs in the field . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

Figure 1. The genotype-resistance index model. . . . . . . . . . . . . . . . . . . . . . . . . . . . 90

Annex 10 WORKING PAPER: Strategies for improved diagnostics for malaria, including rapid diagnosis 93

Annex 11 WORKING PAPER: Plasmodium falciparum – a genome revealed . . . . . . . . . . . . . . . . . . 99

Annex 12 WORKING PAPER: Prospective antimalarial drug discovery and development . . . . . . . . 105

Table 1. Overview of the processes of drug discovery and development . . . . . . . . . . . 107Figure 1. MMV product discovery and development portfolio, with a summary of key partners . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

Annex 13 WORKING PAPER: Malaria vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111

Annex 14 WORKING PAPER: New advances in the development of insecticides . . . . . . . . . . . . . 119

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Annex 15 WORKING PAPER: Sociocultural and behavioural issues in the treatment and prevention of malaria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125

Annex 16 WORKING PAPER: Social, political, economic and inequity issues related to malaria resurgence and inequalities in access to treatment for and prevention of malaria . . . . 133

Annex 17 WORKING PAPER: The economics of malaria and its control. . . . . . . . . . . . . . . . . . . . 139

Annex 18 WORKING PAPER: Achievements, challenges and opportunities in malaria research . . . . 149

Report of the Scientific Working Group on Malaria, 2003 • TDR/SWG/03 1

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Executive summary

Malaria remains a major threat to human health, despite considerable national and international

control efforts. Continued progress in prevention, treatment and the development of innovative

tools for the control of malaria is required.

The Scientific Working Group (SWG), an interdisciplinary group of scientists representing

academic, government and nongovernmental organizations, was assembled to review the cur-

rent state of knowledge and to provide guidance to the UNICEF/UNDP/World Bank/WHO

Special Programme for Research and Training in Tropical Diseases (TDR) and partners regard-

ing challenges that exist and opportunities that could be exploited in areas of research ranging

from basic social science and biomedical sciences to product development and implementa-

tion. Specific capacity building needs and partnership opportunities that are tightly linked to

the research agenda were identified.

The application of scientific discovery and innovation to research on and control of malaria

has been an important function of TDR over the past three decades and the SWG strongly rec-

ommended that TDR should continue in this role. In particular, in consultation with experts

working at the cutting edge of discovery and innovation in basic and applied science, TDR is

able to rapidly identify and implement important advances (e.g. evaluation of insecticide-treat-

ed nets, evaluation of home management of malaria, development of transgenic mosquitoes,

analysis of the ethical, legal and social issues (ELSI) associated with genetically-modified

insect vectors, sequencing of the genomes of Plasmodium falciparum and Anopheles gambiae,

evaluation of artemisinin-containing combination therapies (ACT) for treatment and intermit-

tent preventive treatment (IPT) of malaria in children and in pregnant women). TDR has also

been a leader in capacity building, including developing relevant training in tropical diseases

research and establishing facilities in countries where malaria is endemic. The SWG strongly

recommended that capacity building and training remain integral and central activities of TDR.

The SWG recognized that the funding environment for research on malaria and for the opera-

tional implementation of malaria control measures had changed substantially and that many of

the activities of TDR could now be conducted most productively in collaboration or partner-

ship with other funding agencies or organizations. The SWG thus strongly recommended that

TDR continue to participate in ongoing collaborations and should initiate new relationships

where appropriate synergies exist, particularly in the areas of strategic and basic research,

product development and capacity building. Moreover, the strong foundation of TDR in evi-

dence-based research could provide a framework for the evaluation and monitoring of opera-

tional activities.

Report of the Scientific Working Group on Malaria, 2003 • TDR/SWG/032

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The SWG also recognized the importance of training, capacity building and capacity use in

achieving the aims of the research agenda drawn up by TDR and partners. The SWG encour-

aged TDR to maintain and expand its role as a leader in these areas and further advised that the

respective agendas for training and for research should be tightly coupled, in order to promote

both capacity building and capacity use.


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Recommendations

The SWG identified several key gaps in knowledge of malaria and suggested ways to address

these through a focused agenda of research. In summary, the SWG recommended that the fol-

lowing areas of research should receive special attention:

• Evaluation of treatment and access to treatment for uncomplicated malaria in children and

malaria in pregnant women, with an emphasis on home management of malaria (HMM);

• Evaluation of new approaches to preventing and managing severe malaria;

• Evaluation of artemisinin-based combination therapies (ACT);

• Development of new drugs with novel targets;

• New approaches to drug-based prevention of malaria, including intermittent preventive ther-

apy (IPT) in children and in pregnant women;

• Strategies for scaling up the use of insecticide-treated nets (ITNs);

• Genomic tools for the discovery and development of drug, diagnostics, vaccines, insecti-

cides and anti-parasite effector molecules;

• Strategic and basic research in vector/parasite/host interactions;

• Assessment of the mechanisms of resistance to drugs and insecticides;

• Development and evaluation in the field of transgenic methods for interrupting the transmis-

sion of malaria;

• Investigation of the pathogenesis of malaria, in particular, anaemia and mechanisms of

immune response;

• Development and application of a common methodology for measuring socioeconomic status;

• Policy and operational research on the impact, viability, sustainability and optimal balance in

public–private partnerships (PPP);

• Ethical, legal and social issues raised by new tools related to malaria;

• Continued and expanded capacity building and synergistic partnerships.

Specific recommendations on priorities for research, training and implementation are outlined

in the tables included in this report.


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Introduction

Malaria is a public health problem in more than 90 countries inhabited by approximately 2400

million people, representing about 40% of the population of the world1. Best estimates cur-

rently describe the annual global burden of malaria as: deaths, 1.12 million; clinical cases,

300–500 million; disability-adjusted life years (DALYs), 42.28 million. It has been estimated

that the economic burden of malaria is also extremely high, accounting for a reduction of 1.3%

in the annual economic growth rate of countries in which malaria is endemic, and that the con-

sequent long-term impact is a reduction of gross national product (GNP) of more than half 2.

Malaria is not a uniform disease. It has many manifestations and its impact varies depending

on the epidemiological setting. More than 90% of the burden of disease falls in sub-Saharan

Africa, and almost all deaths attributable to P. falciparum occur in Africa. Most of the remain-

ing burden is distributed between the Indian subcontinent, south-east Asia, Oceania, and the

Americas. After P. falciparum, the second largest burden of disease is caused by P. vivax,

which may cause up to 80 million cases of malaria per year, of which approximately 15%

occur in Africa and 85% outside Africa.

The burden of malaria differs according to age and sex. Almost all deaths occur in children

aged < 5 years in Africa. Although the risk for older children and adults in Africa is reduced

due to development of a degree of immunity to the disease as a result of continuous expo-

sure, outside Africa, where continuous exposure does not occur, the burden of disease extends

into adulthood. Pregnant women, especially primigravidae in Africa, are at high risk, and are

the major risk group of adults in Africa. The disease burden associated with pregnancy has an

additional impact due to the effect of malaria on the health of the fetus.

There is a strong social and economic dimension to the burden of this disease. Those at great-

est risk of malaria are populations that are poor, or that are marginalized, such as ethnic minor-

ities and people displaced as a result of civil unrest.

Major trends over the last few decades suggest that the situation will worsen if effective action

is not taken. These trends include: an increase in epidemics of malaria; upward trends in mor-

tality over the last three decades, including in sub-Saharan Africa; an upward trend in the inci-

dence of malaria caused by drug-resistant P. falciparum; the re-emergence of malaria caused

by P. vivax in areas from which it had been previously eradicated, e.g. in the Caucuses and

central Asia; and an increase in imported malaria in the developed world.

In view of rising trends in the burden of malaria and the difficulties encountered in control of

this disease, a review of research and control activities and future plans is urgently required.

1 WHO, Fact Sheet No 94, revised October 1998, World Health Organization Press Office, Geneva.2 Sachs J, Malaney, P. The economic and social burden of malaria. Nature, 2002, 415(7):680–685.


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1. Objectives and expected outcomes

The aim of the Scientific Working Group (SWG) was to recommend an overall strategy and sci-entific direction for a global research agenda, capacity and partnership building for malaria research for the next five years and beyond. This would provide a basis for TDR to define its own malaria research programme, taking into account its comparative advantages. The objectives of the meeting were:

• To review the current status of and challeng-es in malaria control, and to define the corre-sponding priority research needs;

• To review current efforts in malaria research, and to identify promising research opportuni-ties;

• To identify priority needs to strengthen research capacity and to build partnerships for malaria research and control;

• To examine the gap between needs and existing efforts in research and capacity strengthening;

• To propose a global agenda for malaria research and capacity building that addresses priority needs and promising research oppor-tunities, and to recommend which part of this agenda should be addressed by TDR.

The expected outcomes were:

• Recommendations about an overall strategy and scientific direction for a global research agenda, capacity and partnership building for malaria control for the next five years;

• Definition of priorities among research topics, in order to provide a basis upon which TDR can define its malaria research programme, taking into account its comparative advantages;

• Publication and wide distribution of the SWG meeting report.

The following specific subjects were discussed:

• Current strategic emphases for malaria research in TDR;

• Current strategic emphases for malaria control in the Roll Back Malaria (RBM) global strate-gy for vector control;

• Improved tools and strategies for the treatment of malaria:

– Improved access to treatment and use of antimalarials;

– Improved management of malaria in children (including home management of malaria);

– Improved management of malaria during pregnancy;

– New and improved antimalarial drugs (including therapeutic strategies, overcoming resistance, improving safety and making bet-ter regimens);

– Strategies for improved diagnostics (includ-ing rapid diagnostic tests).

• Improved tools and strategies for the preven-tion of malaria:

– Strategies for scaling up the use of insecti-cide-treated nets (ITNs);

– Research strategies for improving vector control and the monitoring of insecticide resistance and management;

– Strategies for scaling up intermittent preven-tive treatment for malaria and for anaemia in pregnant women and children;

– Improved methods of surveillance and infor-mation management (to monitor and predict resistance to antimalarial drugs and to assess preparedness to face epidemics);

– Strategies to assess impact of new interven-tions.

• Innovative approaches to treatment and pre-vention of malaria:

– Genome sequencing to identify novel targets for drugs, diagnosis and vaccines;


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– Perspective on drug discovery and develop-ment;

– Perspective on the discovery and develop-ment of vaccines;

– Perspective on strategies for the interruption of transmission;

– New advances in the development of insecti-cides.

• Social, economic, behavioural, health systems and policy research for malaria treatment and prevention:

– Social, cultural and behavioural issues asso-ciated with the prevention and treatment of malaria, including illness recognition and home management of febrile illness, social and behavioural issues related to treatment adherence and prevention (impregnated bed-nets), gender issues, behaviour change and community participation;

– Social, political and economic issues relat-ed to malaria resurgence and inequalities of access to treatment and prevention of malaria;

– Economics of malaria and its control, includ-ing economic impact of malaria, cost–effec-

tiveness of interventions, the relationship between malaria control and the health sys-tem, how to strengthen the health system to support malaria control, including interven-tion in both public and private sectors, and economic issues in scaling up prevention and treatment.

Following these discussions, four Working Groups were assembled. The aims of these groups were to:

• Review current strategies for malaria control;

• Identify gaps, challenges and opportunities in malaria research;

• Address capacity and partnership building;

• Recommend the research needed to address the challenges and prioritize the research topics in terms of relevance to TDR and its partners.

The reports of the four Working Groups are sum-marized herewith, together with their recommen-dations for capacity and partnership building, which have been pooled and placed at the end of this report.


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2. Improved tools and strategies for the treatment of malaria

CURRENT STATUS

In areas where malaria is endemic, the primary objective of malaria treatment programmes is to ensure that all patients with uncomplicated malar-ia receive treatment with a safe and effective drug as soon as possible after the onset of their symp-toms. Achieving this goal requires that:

• Patients with malaria, or their guardians, rec-ognize the nature of their illness and seek treatment urgently;

• When a patient with malaria presents at a health facility, a definitive or presumptive diagnosis of malaria is made;

• A source of effective treatment is available near to the patient’s home, from either from a public or a private health-care facility;

• Those providing treatment know the correct dose, and the need to continue treatment for the full course, and dispense the drug in a way that makes it easy for the patient to follow the prescribed course;

• The antimalarial drug provided is effective against local strains of parasites and is of high quality;

• An effective drug-supply system is in place;

• An effective malaria control programme is in place, which is able to monitor the effec-tiveness of treatment and to define a rational, national treatment policy.

Even when treatment programmes are working well, some patients will still progress to com-plicated malaria, often very rapidly; there is thus a need to ensure that all health-care facili-ties to which such patients may present have the expertise and resources to treat these severely-ill patients in an effective manner.

Ensuring that each of these requisites is met at a national scale is a demanding task. Good

progress has been made during the past few years by many countries in which malaria is endem-ic, but research is still needed on ways in which treatment could be provided more effective-ly than at present. This Working Group consid-ered research needs at each level of the treatment pathway.

Diagnosis

It was recognized that, in most parts of Africa, a diagnosis of malaria must be made without the benefit of laboratory support. In such a situa-tion, emphasis should be placed on overall man-agement of the sick children; further work is still needed on optimal ways to incorporate treat-ment of malaria into the integrated management of childhood illness (IMCI) approach, for exam-ple, the use of drugs or drug combinations with both antiparasitic and antibacterial properties. It may be possible to find ways to link treatment for malaria to other child health programmes, for example, linkage of intermittent preventive treat-ment (IPT) to immunization or growth moni-toring programmes. In older children, treatment might be linked to nutrient supplementation or de-worming programmes.

The Working Group considered that tests for rapid diagnosis were unlikely to have a major role in the treatment of malaria in the areas of Africa where malaria is highly endemic and where most healthy children are parasitaemic. Rapid diagnostic tests are likely to be more use-ful in areas of low-to-moderate transmission, especially where treatment requires the use of costly drugs. In many areas of low-to-medium transmission, infections with Plasmodium falci-parum and P. vivax are both found; as these may require different treatments, species-specific tests may be required. The Working Group consid-ered that further research is needed on the devel-opment of rapid diagnostic tests and how they can be used most effectively, but considered that


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this was only of medium priority because of the relatively low overall contribution of malaria in low transmission areas to the burden of malaria worldwide. If current efforts are successful in reducing malaria transmission then the impor-tance of diagnosis will increase correspondingly.

Home management

This Working Group considered that there are still important research questions to be addressed regarding home management, defined as the pro-vision of treatment as near to the home as possi-ble. Areas of research required, overlapping with those identified by the Working Group on soci-oeconomic issues, include how to expand the training of shopkeepers, packaging, and research on how economic decisions are reached at the household level about the purchase of health interventions for common diseases such as malaria. Work in this overall area was considered to be of high priority.

The administration of artesunate by the rec-tal route by community workers or peripheral health-care staff was recognized as a poten-tially important way of reducing mortality from severe malaria. If the results of trials currently under way confirm these expectations, then more research will be needed on how to use this inter-vention most effectively, for example, how to identify children who are most likely to benefit.

Malaria in pregnancy

Treatment of malaria in pregnancy was identi-fied as a priority for research, in view of the fact that drugs such as chloroquine and SP, which have been used widely for this purpose for many years, are no longer effective in many areas in which malaria is endemic. Carefully conducted trials will be needed to demonstrate the safety in pregnancy of combinations of existing antima-larial drugs, particularly those including artem-

isinins, as well as the safety in pregnancy of new drugs. Data on safety and efficacy will be needed for the new drugs and new combinations of drugs in the treatment of pregnant women with para-sitaemia and for their use in IPT. In general, for ethical reasons, new drugs and new combinations of drugs should be investigated first in women who are known to be parasitaemic, before being used in trials of IPT; this is because in trials, the new drug or drug combination will be given to many pregnant women who are not parasitaemic.

Management of severe malaria

In Africa, only a proportion of children with severe malaria receive treatment in hospital; the exact figure varies substantially from area to area. Nevertheless, it should be possible to reduce overall mortality from malaria if man-agement of these children could be improved. Currently, treatment of children with severe malaria is often poor and WHO guidelines are rarely followed. Blood transfusion is often used inappropriately. Research is needed into ways in which this situation could be rectified. In hospi-tals with limited diagnostic resources it is often difficult to differentiate severe malaria from other serious infections in young children, thus research on improving mortality from severe malaria needs to focus on developing better over-all management of the severely ill child.

Antimalarial drug research

Prospects for new antimalarial drugs have improved substantially during the past few years through initiatives such as the Medicines for Malaria Venture (MMV) and some renewal of interest in malaria among some pharmaceutical companies. The P. falciparum genome project is leading to the identification of new drug targets. New drug combinations are being evaluated and several new drugs are in the pipeline. Thus, the Working Group considered that development of


Mal

aria

new drugs is less critical a priority than was the case a few years ago, but that work in this area should still be considered high priority. Priority should be given to the development of antima-larials with a novel mode of action, to those with broad activity across species and, if possible, to those with activity against both asexual and sex-ual stages of the parasite. New drugs should be user-friendly, thus facilitating high levels of com-pliance. Downstream research will be needed to improve the dosing, co-formulation and presen-tation of the recently-introduced more effective drugs so as to optimize their use.

Many new drugs are being developed through some kind of public–private partnership and the Working Group considered that it is impor-tant that research is conducted into the modes of action of different types of public–private part-nerships to determine which have been the most effective and the most cost–effective.

Drug resistance

Spread of drug-resistant parasites may be delayed by the adoption of combination therapies but is likely to be a continuing problem that threatens treatment strategies. Thus, the Working Group considered that research on biological and social factors determining the spread of drug resistance is important and gave this a medium level of pri-ority.

Treatment policy

The Working Group recognized the need for fur-ther research on the most effective ways to deter-mine national policies regarding antimalarial drugs and on how to implement changes in poli-cy once policies have been drawn up.

The Working Group identified a wide variety of research topics, covering a range of academic disciplines, that could help to improve treatment

of malaria. Although many research questions were considered to be of high priority, none was considered to be of overwhelming importance and it was agreed that a broad-based programme of research is needed. The group noted that there is currently no body within WHO that takes over-all responsibility for addressing research issues relevant to the treatment of malaria and that dif-ferent priorities may sometimes be set by differ-ent parts of the Organization. Thus, the group recommended that a broad-based steering com-mittee should be established within WHO to set priorities for the optimal development and deployment of antimalarial drugs. This group could foster research on pragmatic issues, such as drug formulation and dosage, that would not be of interest to the major academic funding bodies.

CHALLENGES AND OPPORTUNITIES

The major challenges concerning strategies for the treatment of malaria include:

Getting the drugs to the sick patient

• Pragmatic therapeutic solutions based on oper-ational reality rather than ideal circumstances;

• Increased emphasis on early treatment (home management);

• Optimizing care-seeking/delivery/adherence/coverage.

Ensuring efficacy of antimalarial drugs

• Move to aim for high cure rates and away from acceptance of ineffective treatments;

• Artemisinin-based combination treatments are the most promising treatments and increasing-ly demanded by countries in which malaria is endemic;

• Drugs must be both efficacious and effective,


Mal

aria

and must be protected from the emergence of resistance;

• Development of new drugs.

Improving implementation

• In areas of stable transmission: improve sup-port for IMCI, and the policy of treatment of all fever in children aged less than five years as malaria;

• In areas of unstable transmission: improve diagnosis and treatment.

Managing severe malaria

• Application of the WHO criteria and guide-lines for management of malaria;

• Quinine is the mainstay of parenteral antima-larial treatment, artemisinin derivatives are alternatives;

• Artesunate rectocaps are being evaluated for efficacy in the prevention and treatment of severe malaria at the village level.

As severe malaria results largely from late or inadequate treatment, behavioural research is needed on how to improve or accelerate the rec-ognition of severe malaria, how to accelerate referral, and how to ensure that adequate initial doses of antimalarial drugs are given by prac-titioners. A standard care package – containing treatment protocols, appropriate drugs, fluids, anticonvulsant, fixed standards for appropriate interventions (e.g. blood transfusions), and other adjunct therapies – needs to be developed and its impact studied. There is a need for follow-up of discharged patients, especially with regard to anaemia.

TDR comparative advantages

The comparative advantages of TDR and partners

represent major opportunities for the improve-ment of strategies for the treatment of malaria.

The comparative advantages of TDR with respect to drug development include:

– Technical input and guidance to MMV and other partners

– Ability to coordinate and to undertake a bridg-ing role between RBM and MMV

– Opportunistic gap-filling

– Private sector participation in product develop-ment teams.

The comparative advantages of TDR’s partners include:

– Funding and prioritization

– Development, undertaken by industry and MMV

– Upstream research and clinical development, undertaken by academia.

More generally, the strengths of TDR are:

– To lead and coordinate projects

– To provide links between countries

– A track record of valuable and important work in this area

– Interactions with other stakeholders

– Ability to establish and maintain multi-disci-plinary matrix teams and to attract expertise to projects.

A legal framework needs to be developed to allow deployment outside the formal health-care sector of effective anti-infective drugs (which are often available by prescription only). The WHO department of Essential Drugs and Medicine Policy (EDM) and RBM need to take the lead to make this happen appropriately.

There has been a lack of alignment on policy and development within WHO with regard to antima-larial drugs that creates uncertainty in countries


Mal

aria

in which malaria is endemic and in the research and development community. This uncertain-ty slows down the process by which new, more effective antimalarial treatments can be brought into use. We now have a number of promis-ing new drugs, both in development and already deployed. Optimizing the choice, development and use of these drugs will require an ongoing practical, flexible and supportive research initi-ative that responds rapidly to needs. To address

this, a cross-platform steering committee should be convened from WHO and its associates to set priorities, advise, and, where necessary, super-vise the optimum development and deployment of antimalarial drugs. The primary objective is to provide malaria control programmes with recom-mendations for combination treatments that are affordable, effective and safe. TDR could play a pivotal role in establishing and leading this com-mittee.

Report of the Scientific Working Group on Malaria, 2003 • TDR/SWG/0312 Report of the Scientific Working Group on Malaria, 2003 • TDR/SWG/0312

Hig

hpr

iori

ty

Rese

arch

for

whi

ch T

DR h

as a

com

para

tive

adv

anta

geAc

tivi

ties

mos

t ap

prop

riat

e fo

r ot

her

part

ners

Unc

ompl

icat

ed m

alar

iaCo

mpa

rati

ve a

sses

smen

ts o

f im

pact

of e

xist

ing

and

new

ant

imal

aria

ls in

clud

ing

stud

ies

on:

• Sa

fety

and

eff

icac

y (i

n H

IV-p

osit

ive

and

HIV

-neg

ativ

e pa

tien

ts)

• Ef

fect

iven

ess

of t

he d

istr

ibut

ion

syst

ems

of a

ntim

alar

ials

• Re

lati

ve a

ttit

udes

, pra

ctic

es, q

ualit

y an

d pe

rfor

man

ce o

f all

trea

tmen

t pr

ovid

ers

(inf

orm

al a

nd fo

rmal

)•

Best

met

hods

of h

ealth

pro

mot

ion,

wit

h em

phas

is o

n th

e ro

le o

f hea

lth-c

are

pers

onne

l, di

spen

sers

, car

e-gi

vers

•

Drug

pac

kagi

ng

• Ac

cess

, inc

ludi

ng p

refe

renc

es fo

r and

bar

riers

to

choi

ce o

f mal

aria

rela

ted

heal

th c

are

• Co

mpl

ianc

e (e

spec

ially

am

ong

poor

est)

• In

tegr

atio

n w

ith

man

agem

ent

of s

ick

child

• Cl

inic

al p

harm

acol

ogic

al a

sses

smen

t

Part

icul

ar e

mph

asis

sho

uld

be p

lace

d on

(1)

Brin

ging

eff

ecti

ve t

reat

men

ts c

lose

r to

the

hom

e an

d (2

) In

vest

igat

ing

the

prio

rity

give

n to

mal

aria

as

a ho

useh

old

prob

lem

.

Mal

aria

dur

ing

preg

nanc

yEv

alua

tion

of t

he s

afet

y an

d ef

ficac

y of

new

ant

imal

aria

l dru

gs in

HIV

-pos

itiv

e an

d H

IV-n

egat

ive

preg

nant

pat

ient

s —

a n

eces

sary

pre

requ

isit

e fo

r eva

luat

ion

of t

hese

dru

gs

in in

term

itte

nt p

reve

ntiv

e tr

eatm

ent

(IPT

).

Seve

re m

alar

iaDe

velo

pmen

t an

d ev

alua

tion

of a

sta

ndar

d m

anag

emen

t pa

ckag

e to

add

ress

mor

talit

y fr

om s

ever

e m

alar

ia in

hea

lth

faci

litie

s, a

nd c

are

afte

r dis

char

ge (

espe

cial

ly w

ith

rega

rd

to a

naem

ia).

If r

ecta

l art

esun

ate

is s

how

n to

be

effe

ctiv

e in

redu

cing

mor

talit

y, re

sear

ch

will

be

need

ed t

o sh

ow h

ow b

est

it c

ould

be

impl

emen

ted.

Nov

el a

gent

sDe

velo

pmen

t of

new

dru

gs b

ased

on

need

s (e

.g. d

rugs

faci

litat

ing

high

com

plia

nce)

and

m

ode

of a

ctio

n (e

.g. f

or s

ever

e m

alar

ia: w

ater

-sol

uble

and

wit

h a

broa

d sp

ecifi

city

of a

ctio

n).

Emph

asis

sho

uld

be o

n dr

ugs

wit

h no

vel t

arge

ts.

Publ

ic–p

riva

te p

artn

ersh

ips

(PPP

)Po

licy

rese

arch

on

the

impa

ct, v

iabi

lity,

sus

tain

abili

ty a

nd o

ptim

al b

alan

ce in

pub

lic–p

rivat

e pa

rtne

rshi

ps fo

r acc

ess

to t

reat

men

t fo

r mal

aria

.

Mal

aria

dur

ing

preg

nanc

yCo

llabo

rate

on

stud

ies

of t

reat

men

t w

ith

new

dru

gs; t

he is

sue

of p

rodu

ct li

abili

ty n

eeds

to

be

addr

esse

d.

Med

ium

pr

iori

tyDi

agno

sis

Whe

n is

it c

ost-

bene

ficia

l to

diag

nose

, and

will

pro

vide

r pra

ctic

e be

influ

ence

d by

im

prov

ed d

iagn

osis

?St

udie

s ar

e ne

eded

in t

he c

onte

xt o

f inc

reas

ingl

y ex

pens

ive

trea

tmen

t sc

hedu

les,

new

di

agno

stic

tes

ts, a

nd a

t di

ffer

ent

leve

ls o

f tra

nsm

issi

on in

tens

ity

and

geog

raph

ic s

etti

ng

(Asi

a, L

atin

Am

eric

a an

d Af

rica)

, in

both

pub

lic a

nd p

rivat

e se

ctor

s.

Resi

stan

ceFa

ctor

s de

term

inin

g th

e em

erge

nce,

spr

ead,

and

the

dec

line

of re

sist

ance

; the

ope

rati

onal

ut

ility

of m

onit

orin

g of

resi

stan

ce, i

nclu

ding

val

idat

ion

and

use

of in

vitr

o an

d m

olec

ular

m

arke

rs; s

igni

fican

ce a

nd im

port

ance

of c

ross

-res

ista

nce;

soc

ial,

beha

viou

ral a

nd e

cono

mic

re

sear

ch o

n hu

man

fact

ors

favo

urin

g th

e em

erge

nce

of d

rug

resi

stan

ce.

Drug

sup

ply

need

sFo

reca

st o

f dem

and

for a

ntim

alar

ials

(es

peci

ally

art

emis

inin

s) w

ith

Roll

Back

Mal

aria

hav

ing

a ce

ntra

l rol

e.

Inte

grat

ion

of s

trat

egie

s fo

r tr

eatm

ent

and

prev

enti

on o

f m

alar

ia w

ith

othe

r ch

ild

heal

th in

itia

tive

s. I

s in

corp

orat

ion

of m

alar

ia in

terv

enti

ons

prac

tica

l and

whi

ch c

hild

hood

pr

ogra

mm

es a

re t

he m

ost

appr

opria

te (

e.g.

IM

CI, de

-wor

min

g pr

ogra

mm

es, EP

I)?

Appl

ied

rese

arch

to

fost

er s

usta

inab

le p

artn

ersh

ips

for m

alar

ia c

ontr

ol w

ith

com

mun

itie

s.Im

plem

enta

tion

rese

arch

to

iden

tify

hum

an re

sour

ce c

onst

rain

ts (

e.g.

att

ritio

n, b

rain

dra

in)

and

its

impa

ct o

n su

stai

ning

nat

ionw

ide

prog

ram

mes

, inc

ludi

ng im

plem

enta

tion

capa

city

of

dist

rict le

vel h

ealth

ser

vice

s.Po

licy

rese

arch

to

inve

stig

ate

the

opti

mal

gov

ernm

ent

invo

lvem

ent

in m

alar

ia c

ontr

ol (

e.g.

dr

ug re

gula

tion

).

Tabl

e 1.

SW

G pr

iori

tiza

tion

of n

eede

d re

sear

ch o

n im

prov

ed t

ools

and

str

ateg

ies

for t

he t

reat

men

t of

mal

aria


Mal

aria

3. Improved tools and strategies for the prevention of malaria

Hig

hpr

iori

ty

Rese

arch

for

whi

ch T

DR h

as a

com

para

tive

adv

anta

geAc

tivi

ties

mos

t ap

prop

riat

e fo

r ot

her

part

ners

Unc

ompl

icat

ed m

alar

iaCo

mpa

rati

ve a

sses

smen

ts o

f im

pact

of e

xist

ing

and

new

ant

imal

aria

ls in

clud

ing

stud

ies

on:

• Sa

fety

and

eff

icac

y (i

n H

IV-p

osit

ive

and

HIV

-neg

ativ

e pa

tien

ts)

• Ef

fect

iven

ess

of t

he d

istr

ibut

ion

syst

ems

of a

ntim

alar

ials

• Re

lati

ve a

ttit

udes

, pra

ctic

es, q

ualit

y an

d pe

rfor

man

ce o

f all

trea

tmen

t pr

ovid

ers

(inf

orm

al a

nd fo

rmal

)•

Best

met

hods

of h

ealth

pro

mot

ion,

wit

h em

phas

is o

n th

e ro

le o

f hea

lth-c

are

pers

onne

l, di

spen

sers

, car

e-gi

vers

•

Drug

pac

kagi

ng

• Ac

cess

, inc

ludi

ng p

refe

renc

es fo

r and

bar

riers

to

choi

ce o

f mal

aria

rela

ted

heal

th c

are

• Co

mpl

ianc

e (e

spec

ially

am

ong

poor

est)

• In

tegr

atio

n w

ith

man

agem

ent

of s

ick

child

• Cl

inic

al p

harm

acol

ogic

al a

sses

smen

t

Part

icul

ar e

mph

asis

sho

uld

be p

lace

d on

(1)

Brin

ging

eff

ecti

ve t

reat

men

ts c

lose

r to

the

hom

e an

d (2

) In

vest

igat

ing

the

prio

rity

give

n to

mal

aria

as

a ho

useh

old

prob

lem

.

Mal

aria

dur

ing

preg

nanc

yEv

alua

tion

of t

he s

afet

y an

d ef

ficac

y of

new

ant

imal

aria

l dru

gs in

HIV

-pos

itiv

e an

d H

IV-n

egat

ive

preg

nant

pat

ient

s —

a n

eces

sary

pre

requ

isit

e fo

r eva

luat

ion

of t

hese

dru

gs

in in

term

itte

nt p

reve

ntiv

e tr

eatm

ent

(IPT

).

Seve

re m

alar

iaDe

velo

pmen

t an

d ev

alua

tion

of a

sta

ndar

d m

anag

emen

t pa

ckag

e to

add

ress

mor

talit

y fr

om s

ever

e m

alar

ia in

hea

lth

faci

litie

s, a

nd c

are

afte

r dis

char

ge (

espe

cial

ly w

ith

rega

rd

to a

naem

ia).

If r

ecta

l art

esun

ate

is s

how

n to

be

effe

ctiv

e in

redu

cing

mor

talit

y, re

sear

ch

will

be

need

ed t

o sh

ow h

ow b

est

it c

ould

be

impl

emen

ted.

Nov

el a

gent

sDe

velo

pmen

t of

new

dru

gs b

ased

on

need

s (e

.g. d

rugs

faci

litat

ing

high

com

plia

nce)

and

m

ode

of a

ctio

n (e

.g. f

or s

ever

e m

alar

ia: w

ater

-sol

uble

and

wit

h a

broa

d sp

ecifi

city

of a

ctio

n).

Emph

asis

sho

uld

be o

n dr

ugs

wit

h no

vel t

arge

ts.

Publ

ic–p

riva

te p

artn

ersh

ips

(PPP

)Po

licy

rese

arch

on

the

impa

ct, v

iabi

lity,

sus

tain

abili

ty a

nd o

ptim

al b

alan

ce in

pub

lic–p

rivat

e pa

rtne

rshi

ps fo

r acc

ess

to t

reat

men

t fo

r mal

aria

.

Mal

aria

dur

ing

preg

nanc

yCo

llabo

rate

on

stud

ies

of t

reat

men

t w

ith

new

dru

gs; t

he is

sue

of p

rodu

ct li

abili

ty n

eeds

to

be

addr

esse

d.

Med

ium

pr

iori

tyDi

agno

sis

Whe

n is

it c

ost-

bene

ficia

l to

diag

nose

, and

will

pro

vide

r pra

ctic

e be

influ

ence

d by

im

prov

ed d

iagn

osis

?St

udie

s ar

e ne

eded

in t

he c

onte

xt o

f inc

reas

ingl

y ex

pens

ive

trea

tmen

t sc

hedu

les,

new

di

agno

stic

tes

ts, a

nd a

t di

ffer

ent

leve

ls o

f tra

nsm

issi

on in

tens

ity

and

geog

raph

ic s

etti

ng

(Asi

a, L

atin

Am

eric

a an

d Af

rica)

, in

both

pub

lic a

nd p

rivat

e se

ctor

s.

Resi

stan

ceFa

ctor

s de

term

inin

g th

e em

erge

nce,

spr

ead,

and

the

dec

line

of re

sist

ance

; the

ope

rati

onal

ut

ility

of m

onit

orin

g of

resi

stan

ce, i

nclu

ding

val

idat

ion

and

use

of in

vitr

o an

d m

olec

ular

m

arke

rs; s

igni

fican

ce a

nd im

port

ance

of c

ross

-res

ista

nce;

soc

ial,

beha

viou

ral a

nd e

cono

mic

re

sear

ch o

n hu

man

fact

ors

favo

urin

g th

e em

erge

nce

of d

rug

resi

stan

ce.

Drug

sup

ply

need

sFo

reca

st o

f dem

and

for a

ntim

alar

ials

(es

peci

ally

art

emis

inin

s) w

ith

Roll

Back

Mal

aria

hav

ing

a ce

ntra

l rol

e.

Inte

grat

ion

of s

trat

egie

s fo

r tr

eatm

ent

and

prev

enti

on o

f m

alar

ia w

ith

othe

r ch

ild

heal

th in

itia

tive

s. I

s in

corp

orat

ion

of m

alar

ia in

terv

enti

ons

prac

tica

l and

whi

ch c

hild

hood

pr

ogra

mm

es a

re t

he m

ost

appr

opria

te (

e.g.

IM

CI, de

-wor

min

g pr

ogra

mm

es, EP

I)?

Appl

ied

rese

arch

to

fost

er s

usta

inab

le p

artn

ersh

ips

for m

alar

ia c

ontr

ol w

ith

com

mun

itie

s.Im

plem

enta

tion

rese

arch

to

iden

tify

hum

an re

sour

ce c

onst

rain

ts (

e.g.

att

ritio

n, b

rain

dra

in)

and

its

impa

ct o

n su

stai

ning

nat

ionw

ide

prog

ram

mes

, inc

ludi

ng im

plem

enta

tion

capa

city

of

dist

rict le

vel h

ealth

ser

vice

s.Po

licy

rese

arch

to

inve

stig

ate

the

opti

mal

gov

ernm

ent

invo

lvem

ent

in m

alar

ia c

ontr

ol (

e.g.

dr

ug re

gula

tion

).

CURRENT STATUS

The Global Strategy for Malaria Control stress-es the selective use of preventive measures. Two major risk groups have been identified in this context: pregnant women and infants. The cur-rently available and effective tools for preven-tion are limited to vector control and drug-based interventions.

Drug-based interventions

ChemoprophylaxisRegular chemoprophylaxis is presently recom-mended for non-immune visitors to countries where malaria is endemic and for individuals with sickle-cell anaemia, and is considered for the prevention of infection with P. vivax during pregnancy. Chemoprophylaxis was previously rec-ommended for larger population groups (e.g. chil-dren in areas where malaria is endemic) and was shown to reduce morbidity and mortality in chil-dren, and low birth weight and maternal anaemia in pregnant women. However, several constraints have limited the widespread implementation of chemoprophylaxis, including low compliance, dif-ficulties in the delivery system, high cost, and the fear of increasing drug resistance.

Intermittent preventive treatment in pregnancy Intermittent preventive treatment (IPT) in preg-nancy has been identified as a means to prevent malaria in the two major risk groups, preg-nant women and infants. This strategy has been assessed in a few studies in pregnant women and, although not yet fully evaluated, it has already been recommended for the prevention of malar-ia during pregnancy. Until now, treatment with sulphadoxine/pyrimethamine (SP), because of its low cost and simplicity of use, has been the only option considered. This strategy is a promising

tool for the prevention of malaria in infants, on the basis of a single trial, and is currently under evaluation.

There is a lack of information on the efficacy of IPT-SP in pregnant women in different epide-miological settings, for example, in areas where malaria occurs on a highly seasonal basis or with a low rate of transmission. There is an urgent need to assess the efficacy of drugs other than SP for IPT in pregnancy. It is also essential to evalu-ate the possible role of short-acting drugs as IPT for the prevention of malaria during pregnancy.

Folic acid supplements are recommended for pregnant women. The results of a study in chil-dren suggest that the efficacy of treatment with SP is reduced when there is a concomitant intake of folate. It is therefore necessary to eval-uate the potential interaction between the two drugs. Cotrimoxazole is increasingly recom-mended for the prophylaxis of pneumonia caused by Pneumocystis carinii in individuals infected with the human immunodeficiency virus (HIV). Because cotrimoxazole and SP are both sulfona-mide-based drugs, it is inadvisable to administer IPT with SP to a woman who is already receiv-ing cotrimoxazole. There is need to determine whether such women are adequately protected from malaria by cotrimoxazole, or whether they should receive a safe alternative drug for IPT.

Evaluation of the coverage of IPT-SP in Kenya and Malawi shows that although a high propor-tion (70–95%) of women attending antenatal care clinics received the first dose, only 10–40% of women received a second dose. Operations research into ways to increase coverage and early use of antenatal care services is required.

Assessing the efficacy of antimalarial inter-ventions in pregnant women is difficult and standardized guidelines to determine the best indicators are required.


Mal

aria

There is currently no information on the effica-cy of combined malaria preventive interventions (e.g. ITNs plus IPT).

The use of IPT-SP is recommended after the first trimester of pregnancy. However, a number of women will appear at the antenatal clinic at an earlier stage in pregnancy and there is present-ly no clear recommendation for the prevention of malaria at this stage.

Intermittent preventive treatment in childrenThe use of IPT is a very promising tool for the prevention of malaria in infants in Africa. The findings of the first studies need to be confirmed in other settings in which malaria is endem-ic. Several aspects need to be fully investigated before IPT can be recommended on a widespread basis, including:

– safety

– mode of action

– interactions with vaccines administered as part of the Expanded Programme on Immunization (EPI)

– impact on immunity to malaria

– impact on drug resistance

– efficacy of combined interventions (e.g. ITNs)

– cost–effectiveness

– acceptability.

There is a need to consider alternatives to SP for use in infants, as for IPT-SP in pregnancy

Vector control

Historically, control of the Anopheles vectors of malaria has been the main method for preven-tion of malaria. Indoor residual spraying (IRS) and larval control (by chemical and non-chemical means) are methods that still have roles to play

in prevention, and exact definition of these roles is important.

In recent years, and especially for low-income countries in Africa and south-east Asia, the treat-ment of bednets with pyrethroid insecticides has proved feasible and effective. Treatment with pyrethroids improves the personal protection given by bednets against late-night biting mos-quitoes and, when used throughout a community, these insecticide-treated nets (ITNs) can reduce the infective biting population of mosquitoes. More data are required on the relative contribu-tion of the personal and community elements of the protective effect, which is important for the design of intervention strategies.

There has been concern that the use of only pyre-throids for the treatment of bednets exposes this method to the risk of evolution of resistance to pyrethroids among the vectors. However, some data from West Africa indicate that treated bed-nets are effective even in the presence of a high frequency of a gene conferring resistance. This topic needs further study.

There remain some gaps in knowledge of the epidemiological protection given by bednets. Most of the bednets currently used in Africa are untreated, and too little is known about the degree of protection they provide against malaria. More information is needed about the epidemio-logical significance of entomological measures of the persistence of insecticides on nets.

Most epidemiological studies of field trials of treated bednets have been operated on the basis of free distribution and treatment. There are dif-ferent opinions as to whether such methods could be scaled up to the national and regional level, or whether it would be necessary to rely on subsi-dies targeted at especially vulnerable groups, and complemented by the private sector. The ques-


Mal

aria

tion of how to scale up the use of treated bednets in the most efficient, equitable and sustainable fashion should be of highest priority. It is recom-mended that TDR or RBM should initiate and lead a consortium or partnership, comprising major donors to ITN programmes, to formulate and coordinate a comprehensive plan of research on these issues.

IMPROVEMENT OF PARTNERSHIP

Better understanding of realities in the field, the constraints, and the needs of control programmes would help to rapidly fill some important gaps.

In many cases, the research agenda is driv-en too strongly by that of partners in industrial-ized countries, as opposed to by the needs of the control programmes. Far too few research find-ings are useful for, and applied by, organizations involved in malaria control.

Operational research on strategies for the distri-bution of ITNs, which has been identified as a high research priority, would be best tackled by a consortium or partnership. Such a partnership might include funding agencies, implementation agencies and research institutions. It would most appropriately be led by TDR or RBM.


Tabl

e 2.

SW

G pr

iori

tiza

tion

of n

eede

d re

sear

ch o

n im

prov

ed t

ools

and

str

ateg

ies

for t

he p

reve

ntio

n of

mal

aria

Hig

hpr

iori

ty

Rese

arch

for

whi

ch T

DR h

as a

com

para

tive

adv

anta

geAc

tivi

ties

mos

t ap

prop

riat

e fo

r ot

her

part

ners

Inte

rmit

tent

pre

vent

ive

ther

apy

(IPT

)As

sess

men

t of

mec

hani

sms

of a

ctio

n of

IPT

in p

regn

ancy

and

in

fant

s (i

nclu

ding

sho

rt-

vers

us lo

ng-a

ctin

g dr

ugs)

Alte

rnat

ives

to

the

curr

ent

SP r

egim

en

• Al

tern

ativ

e do

sing

for S

P•

Othe

r dru

gs•

For H

IV-p

osit

ive

pati

ents

Inte

ract

ions

of

SP u

sed

in I

PT w

ith

othe

r dru

gs (

e.g.

fola

te,

cotr

imox

azol

e) a

nd v

acci

nes

(EPI

, tet

anus

tox

oid

in p

regn

ancy

)

Cont

rol o

f m

alar

ia in

pre

gnan

t w

omen

in a

reas

of

low

tra

nsm

issi

onFe

asib

le a

nd m

ost

cost

-eff

ecti

ve in

terv

enti

ons

Inse

ctic

ide-

trea

ted

bedn

ets

(ITN

s)•

Rela

tion

ship

bet

wee

n co

vera

ge a

nd e

pide

mio

logi

cal i

mpa

ct: m

ass

effe

ct v

s pe

rson

al p

rote

ctio

n (i

nclu

ding

unt

reat

ed n

ets)

.•

Com

parin

g an

d st

anda

rdiz

ing

chem

ical

, ent

omol

ogic

al b

ioas

say

and

epid

emio

logi

cal

mea

sure

s of

the

eff

icac

y of

ITN

s, a

nd e

spec

ially

long

-las

ting

net

s. T

his

shou

ld

incl

ude

bett

er p

roxy

mea

sure

s fo

r ass

essi

ng t

he u

se li

fe o

f lon

g-la

stin

g ne

ts.

Inte

rmit

tent

pre

vent

ive

ther

apy

(IPT

)•

Proo

f of p

rinci

ple

stud

ies

for I

PT in

infa

ncy

and

early

chi

ldho

od•

Impr

ovem

ent

of im

plem

enta

tion

of I

PT in

pre

gnan

cy, o

pera

tion

al o

ptim

isat

ion

• Ef

ficac

y of

mul

tipl

e in

terv

enti

ons

(e.g

. IPT

wit

h IT

Ns)

incl

udin

g im

pact

on

imm

unit

y.

Inse

ctic

ide-

trea

ted

bedn

ets

(ITN

s)•

Com

para

tive

mul

ti-d

isci

plin

ary

rese

arch

eva

luat

ing

the

scal

ing

up o

f IT

N an

d ta

rget

ing

inte

rven

tion

s, in

clud

ing

the

follo

win

g m

odel

s:–

Free

net

s an

d in

sect

icid

e tr

eatm

ent

for a

ll–

Targ

etin

g–

Vouc

hers

– Pr

ivat

e se

ctor

– Us

e in

epi

dem

ics

w

ith

emph

asis

on

effic

ienc

y, e

quit

y an

d su

stai

nabi

lity,

and

on

inte

ract

ions

be

twee

n co

-exi

stin

g di

strib

utio

n sy

stem

s (c

onso

rtiu

m le

d by

TDR

).•

Wor

k w

ould

incl

ude

the

follo

win

g as

pect

s: d

eman

d-si

de in

terv

enti

ons;

sup

ply

side

inte

rven

tion

s; t

arge

ting

ITN

s to

spe

cific

gro

ups;

pol

icy

rese

arch

on

the

viab

ility

, sus

tain

abili

ty a

nd o

ptim

al b

alan

ce in

pub

lic–p

rivat

e pa

rtne

rshi

ps.

Indo

or re

sidu

al s

pray

ing

(IRS

)•

Com

para

tive

adv

anta

ges

of I

RS a

nd I

TNs

in s

peci

fic s

itua

tion

s•

Targ

etin

g of

IRS

in t

ime

and

spac

e, in

clud

ing

resp

onse

to

epid

emic

s

Med

ium

pr

iori

tyIP

T •

Prev

enti

on o

f mal

aria

in t

he fi

rst

trim

este

r of p

regn

ancy

.•

Cont

rol o

f mal

aria

in in

fant

s in

are

as o

f low

and

/or P

. viv

ax t

rans

mis

sion

•

Cont

rol o

f mal

aria

in p

regn

ant

wom

en, f

or P

. viv

ax•

Impa

ct o

n an

d of

dru

g re

sist

ance

of I

PT.

ITN

s•

Whe

n an

d w

here

is re

sist

ance

to

pyre

thro

ids

impo

rtan

t an

d ho

w c

an it

be

man

aged

? •

The

valu

e of

inse

ctic

ide

mix

ture

s fo

r tre

atm

ent

of b

edne

ts.

IPT

Cost

–eff

ecti

vene

ss a

nd a

ccep

tabi

lity

in t

he la

rge-

scal

e im

plem

enta

tion

of I

PT.

Appl

ied

rese

arch

to

fost

er s

usta

inab

le p

artn

ersh

ips

wit

h co

mm

unit

ies.

Polic

y re

sear

ch t

o in

vest

igat

e th

e op

tim

al g

over

nmen

t in

volv

emen

t in

vec

tor

cont

rol (

e.g.

opt

imal

pub

lic–p

rivat

e se

ctor

mix

in I

TN d

eliv

ery

mod

els)

.

Inte

grat

ed v

ecto

r man

agem

ent

in u

rban

Afr

ica

and

othe

r sui

tabl

e se

ttin

gs: w

hat

wor

ks, w

hat

does

not

, wit

h em

phas

is o

n ch

emic

al a

nd n

on-c

hem

ical

larv

al c

ontr

ol.


Mal

aria

CURRENT STRATEGIES

The recent publication of the human, mosquito and parasite genomes provides the opportunity to explore new areas of research in drugs, diagnos-tics, vaccines, insecticides, and genetic manipu-lation of vectors. Genomics and bioinformatics can be applied to areas of basic malaria research, such as parasite biology, vector/human/parasite interactions, population biology and immunity. There is a need for increased participation of sci-entists from disease-endemic countries in these efforts.

Malaria is the result of complex interactions between the human host, the mosquito vector and the parasite itself. The ability of the parasite to successfully invade, survive and multiply in dif-ferent host cells determines the outcome of the infection. The level and nature of the immune response of the host has a major impact not only on the survival of the invading parasite but also on the severity and transmission of the disease. Mosquito behaviour, responses to the parasite and longevity determine successful transmission. A better understanding of each of these co-evolv-ing segments of the parasite life cycle will yield novel tools for the control of malaria.

Recent progress in malaria vaccines has been encouraging, and boosted by significant increases in public–private funding. Twelve candidate vac-cines are scheduled for clinical trials and some have shown degrees of efficacy in phase 1 and 2 trials. Vaccines under development include:

– Vaccines that target the pre-erythrocytic stage: a chimeric vaccine composed of a fragment of the P. falciparum circumsporozoite protein (CSP) fused to the surface protein of the hep-atitis B virus; a vaccine containing a synthetic multiple-antigen peptide (MAP) from the cir-cumsporozoite protein; DNA-based vaccines carrying P. falciparum thrombospondin relat-

ed adhesion protein (TRAP) and other antigens boosted by recombinant viruses.

– Vaccines that target the blood stage of the par-asite: a recombinant merozoite surface protein fragment (MSP-142) vaccine; synthetic pep-tides of the P. falciparum merozoite surface protein (MSP-3) or the glutamine rich protein (GLURP), erythrocyte binding protein (EBA-175) from P. falciparum, and the Duffy bind-ing protein from P. vivax.

– Transmission-blocking vaccines: the 25kDa gametocyte antigens of P. falciparum and P. vivax. Several other vaccine candidates with strong evidence of immunogenicity and effica-cy in animal models are in developmental stag-es of preclinical trials.

Chemotherapy is a key control measure for malaria today. The development of resistance to most of the available antimalarial drugs has resulted in the urgent need to understand the mechanisms of drug resistance and for the dis-covery of new drugs. Costs and compliance are also major issues. Current drug development efforts aimed at overcoming some of these lim-itations are focused on combination therapies (largely artemisinin-based combinations) and improvement on existing classes for short- and medium-term impact. Innovative strategies for the discovery of new chemical entities for long-term impact are needed. Genomics is facilitating the identification and validation of new targets that will hopefully benefit from chemistry and high-throughput screening. Natural products have historically contributed to the development of antimalarial drugs, and need to be given more attention. It is important that scientists from dis-ease-endemic countries get involved at all levels.

Early diagnosis and treatment are fundamen-tal to the management of morbidity and mortal-ity caused by malaria. However, poor diagnosis continues to hinder effective control. Clinical

4. Innovative approaches to the control and prevention of malaria


Mal

aria

diagnosis is the most widely used method today. Although this method is sensitive, it is not very specific. Conventional light microscopy has been the established “gold standard” for many years but its use is limited due to the facilities and skilled personnel required to achieve good results. Other newer approaches using molecular or serological techniques are available. However the disadvantages of these methods include cost, and the need for special equipment and labile reagents. There is therefore a need for low cost, stable, sensitive, species-specific rapid diagnos-tic tests.

There is urgent need to develop novel weap-ons to fight malaria. One of them is the genet-ic modification of mosquitoes to decrease their vectorial capacity. Significant progress has been recently made toward this goal. Robust proce-dures to introduce foreign genes into the germ-line of anopheline mosquitoes are now available. Strong promoters that drive the expression of for-eign genes in the mosquito midgut and fat body have been characterized. Moreover, effector gene products that interfere with the development of Plasmodium in the mosquito have been identi-fied. Importantly, proof-of-principle demonstra-tion that mosquitoes can be genetically modified to impair transmission of the malaria parasite has recently been achieved. However, major chal-lenges need to be overcome before this strategy can be implemented in the field.

Insecticides form an integral part of most nation-al malaria control programmes and yet the number of chemical classes suitable for public health applications is severely limited. Resistance to these insecticides, in particular dichloro-diphe-nyl-trichloroethane (DDT) and pyrethroids, is threatening the efficacy of many vector con-trol strategies. Understanding the mechanisms of insecticide resistance and monitoring the fre-quency of resistant alleles is a high priority. The

completion of the sequence of the Anopheles gambiae genome will enable approaches using functional genomics to be applied to expand the tools available for vector control.

Important progress in knowledge of the patho-genesis of severe malaria was made with the identification of multigenic families encoding variant antigens involved in the process of P. fal-ciparum sequestration that is associated with pathological effects. The role of allele-specific interaction with receptors present in endothelial cells of blood vessels in the brain, lungs, kidney or placenta is proposed to explain the different pathologies of severe malaria. However, these and other aspects of parasite virulence, in partic-ular the pathogenesis of anaemia, remain to be better understood. Studies on the pathophysiolo-gy of vivax malaria have been also less empha-sized.

GAPS AND OPPORTUNITIES

Cross-cutting approaches

Genomics and bioinformaticsThe availability of the sequences of the human, Anopheles and Plasmodium genomes pro-vides novel opportunities for malaria research. Question-driven approaches are needed to max-imize the benefits accrued from these advances. High priority areas include: functional genom-ic characterization of field isolates of parasite; analysis of human genetic susceptibility (includ-ing use of the haplotype map of the human genome: HapMap); genomic analysis of sympat-ric mosquito populations; functional genomics of Anopheles to identify new insecticide targets and comparative genomics among anopheline and plasmodial species with the aim of devel-oping model systems. A major gap exists in


Mal

aria

the capacity of developing countries to address issues in genomics and bioinformatics. Following the acquisition of such capacity, sub-Saharan Africa needs to develop its own repository of reagents in regional centres that are satellites for the Malaria Research and Reference Reagent Resource Center (MR4).

Population biologyGaps exist in our understanding of the population biology of both anopheline and plasmodial spe-cies. Gene flow within vector and parasite popu-lations requires further elucidation, for example, in order to enhance understanding of vector pop-ulation dynamics in response to environmen-tal changes. The genetic variability of parasites requires further study to better understand drug resistance and pathology. Transmission dynamics is of relevance in understanding infectivity pat-terns and parasite reservoirs, and also in relation to factors that increase transmission potential. The availability of high-throughput sequenc-ing of human genomes will facilitate the study of variations in susceptibility to disease.

Vector/host/parasite interactionsThere are gaps in knowledge of insect immune/defence mechanisms and of the human response to infection. Mechanisms of cell invasion in mosquitoes and humans need further research. Metabolic interactions between parasite and host are not clearly understood and such studies may identify targets for interventions (drugs and vac-cines). Improvement of culture systems and of laboratory models for parasites would facili-tate testing of current and new interventions and therefore warrants further development.

Parasite-based interventions

Vaccines• Trial-related approaches: In vaccine trials, end-

points such as mortality, morbidity and para-sitaemia are insufficient; there is therefore a need to identify new, well-correlated markers of efficacy. Improved methods of presentation and delivery to induce appropriate immune responses are needed. The value of combining transmission-blocking vaccines with vaccines against either blood- or pre-erythrocytic stages of the parasite, or combining vaccines against different parasite species has been recognized. Experimental design and means of testing the efficacy of these vaccines are needed.

• Mechanisms of natural immune responses: Studies on primary field samples are needed to address the influence of co-infections with parasites, bacteria or viruses on the immune response to malaria and on mechanisms of spontaneous clearance of parasites.

Chemotherapy• Improved models for drug testing: Improved

models should be developed, taking into con-sideration the need for assays of drug suscep-tibility in vitro and for the use of new markers for high-throughput qualitative and quantita-tive estimation of parasite viability, to replace microscopy. Animal models to evaluate para-site viability should include humanized mouse models for P. falciparum.

• New drugs for novel targets: There is a need to develop new drugs for specific targets, includ-ing transmission blocking, as well as those tar-geting the liver-specific stages of the parasite. Functional and chemical genomic tools will assist in the validation of these targets. A bet-ter understanding of the mechanisms of drug resistance, including the use of single nucle-otide polymorphisms (SNPs), would assist in


Mal

aria

the development of markers of and assays for resistance.

• Drug discovery: The setting up of region-al facilities for promoting the development of drugs based on natural products is encouraged. Screening centres for the development of natu-ral products as antimalarial supportive therapy should be established.

Diagnosis and surveillanceRapid and sensitive, species-specific, stable diag-nostic tests are needed. In addition, rapid assays are needed for the quantification of drug levels as well as for glucose-6-phosphate dehydrogenase (G6PD) deficiency in patients infected with P. vivax.

Pathogenesis

• Identification of virulence factors in Plas-modium, taking advantage of genomic tools.

• Analysis of the pathogenesis of severe malar-ia and the physiopathology of infection with P. vivax: Achievements in molecular medicine should be applied to understanding the patho-genesis of severe malaria, with a particular emphasis on anaemia but also on clarifying the mechanisms of cerebral malaria, neurosequelae and malaria in pregnancy.

• Interactions between concomitant infections: The effect of concomitant infection with mul-tiple species of malaria parasite or with other infectious agents, including HIV and tubercu-losis, needs to be addressed.

Vector-based interventions

Genetic manipulation of the competence of mosquito vectors • Approaches for driving genes into populations:

While the feasibility of manipulating the com-petence of mosquito vectors by introduction of genes into the germline has been demon-

strated, little is known about how to introduce such genes into field populations. Possible approaches include:

– Transposable elements: the search for meth-ods based on the use of transposons, such as the Drosophila P element, to introduce foreign genes into a mosquito population should receive high priority;

– Symbiotic bacteria: the possibility of using symbionts to drive genes into populations should be explored;

– Meiotic drive: population replacement can be driven by certain genes, such as the seg-regation distorter gene in Drosophila. Unfortunately, very little is known about such genes in mosquitoes. The identification of such genes could lead to the development of procedures to drive genes into populations.

• New effector genes that interfere with par-asite development in the mosquito and with host-seeking behaviour: While some genes have been identified that are capable of inter-fering with the development of Plasmodium in mosquitoes, they are not 100% effective. Moreover, it is essential that multiple effector genes are employed, in order to minimize the possibility of selecting for resistant parasites. The manipulation of insect behaviour using transgenes should also be considered. The dis-covery of new effector genes for the genet-ic modification of mosquitoes should receive a high priority.

• Understanding of population structure and incipient species gene flow: Understanding of the structure of mosquito populations will be important for the introduction of genetically modified mosquitoes in the field.

• Field tests for transgenic mosquito fitness: While testing for mosquito fitness in labora-tory cage experiments is straightforward, fit-ness should also be evaluated in more realistic


Mal

aria

field conditions under which other factors may come into play.

• Controlled release of transgenic mosquitoes in ecological islands: As a first step to meas-ure the effectiveness of transgenic mosqui-to-based interventions in the field, population replacement by inundatory release should be considered. This would entail the reduction of existent mosquito populations in an ecological-ly isolated area, followed by release of genet-ically modified mosquitoes to populate the vacated niche. The effect on malaria transmis-sion would then be measured.

• Ethical, legal and social implications (ELSI): It is essential that the public at large, government officials and scientists of the countries affected by malaria, be involved in discussions about the benefits and risks of approaches involving the introduction of genetically modified mos-quitoes into the field. As shown by the contro-versy over genetically modified food, this is a difficult and long-term project.

• Methods for maintaining mosquito strains in the laboratory: Maintenance of a large number of mosquito strains, including transgenic mos-quitoes, is a daunting task that consumes enor-mous quantities of labour and resources. The development of innovative methods of keep-ing such strains, such as cryopreservation of embryos, is a difficult but very important goal for the scientific community.

Insecticide resistance and development of novel insecticides• Measurements of the extent and epidemiolog-

ical end-points of insecticide resistance: There is an urgent need to assess the epidemiologi-cal end-points of resistance to insecticides, i.e. what effect do current levels of resistance have on control operations, in particular ITNs and IRS? Further data are needed on the extent of

resistance to insecticides in Anopheles and on patterns of cross-resistance.

• Development of new insecticide products: There is a critical need to develop novel insec-ticides to replace existing products in areas where resistance has rendered these obso-lete, or to incorporate novel insecticides into resistance management programmes in order to extend the operational lifespan of existing insecticides. Studies of functional and compar-ative genomics using data generated by both the Anopheles gambiae and D. melanogaster genome projects will facilitate the identifica-tion of novel targets. Studies on the metabo-lism in insects of existing insecticides should be encouraged to help identify specific inhibi-tors of these pathways that may be developed as insecticide synergists. Also, further atten-tion should be given to the screening of natural products for insecticidal properties. Biological control should be further explored for applica-tion in particular circumstances e.g. larvicides for malaria control in urban areas. Application of the techniques of functional genomics to understanding of the biological basis of anthro-pophily may lead to the development of a new generation of attractants and repellents.

• Establishment of public-health focused insec-ticide discovery and development programmes with capacity to produce adequate quantities of insecticide for public health use.

• Improved monitoring tools for insecticide resist-ance: Accurate and sensitive assays to detect alleles that confer resistance are lacking for some mechanisms of resistance to insecticides.


Tabl

e 3.

SW

G pr

iori

tiza

tion

of n

eede

d re

sear

ch o

n in

nova

tive

app

roac

hes

to m

alar

ia c

ontr

ol a

nd p

reve

ntio

n

Hig

hpr

iori

ty

Rese

arch

for

whi

ch T

DR h

as a

com

para

tive

adv

anta

geAc

tivi

ties

mos

t ap

prop

riat

e fo

r ot

her

part

ners

Geno

mic

s/bi

oinf

orm

atic

sFu

ncti

onal

and

com

para

tive

gen

omic

s us

ing

reag

ent

repo

sito

ry fo

r the

di

scov

ery

and

deve

lopm

ent

of n

ew a

nd im

prov

ed d

rugs

, ins

ecti

cide

s, a

nti-

para

site

eff

ecto

r mol

ecul

es, v

acci

nes

and

diag

nost

ic d

isco

very

.

Chem

othe

rapy

Mec

hani

sm o

f act

ion

and

deve

lopm

ent

of re

sist

ance

; tra

nsm

issi

on-b

lock

ing

drug

s.

Para

site

/hos

t/ve

ctor

inte

ract

ions

Unde

rsta

ndin

g ce

ll in

vasi

on, i

nclu

ding

dev

elop

men

t of

mod

els.

Vacc

ines

Mec

hani

sms

of im

mun

e re

spon

se in

pop

ulat

ion-

base

d st

udie

s; s

elec

tive

dev

elop

men

t re

sear

ch.

Tran

sgen

ics

Cont

rolle

d re

leas

e an

d te

st o

f fit

ness

of t

rans

geni

c m

osqu

itoe

s.

Path

ogen

esis

Mec

hani

sms

of p

atho

gene

sis

in s

ever

e m

alar

ia, w

ith

emph

asis

on

anae

mia

.

Popu

lati

on b

iolo

gyHu

man

, vec

tor a

nd p

aras

ite

gene

tic

poly

mor

phis

ms

rele

vant

to

dise

ase.

Chem

othe

rapy

Scre

enin

g an

d de

velo

pmen

t fo

r lib

rarie

s of

nat

ural

pro

duct

s an

d ch

emic

al c

ompo

unds

; liv

er-s

peci

fic d

rugs

, wit

h em

phas

is o

n P.

viv

ax.

Diag

nosi

sRa

pid

diag

nost

ic t

echn

olog

y.

Popu

lati

on b

iolo

gyGe

neti

c st

ruct

ure,

gen

e flo

w v

ecto

rs/p

aras

ites

.

Vacc

ines

Surr

ogat

e m

arke

r, co

mbi

nati

on v

acci

nes,

exp

erim

enta

l mod

els.

Inse

ctic

ides

, rep

elle

nt/a

ttra

ctan

tsPu

blic

con

sort

ium

for n

ew d

evel

opm

ents

.

Tran

sgen

ics

Ethi

cal,

lega

l and

soc

ial i

ssue

s (E

LSI)

.

Med

ium

prio

rity

Geno

mic

s/bi

oinf

orm

atic

sAn

alys

is o

f gen

etic

var

iati

on (

isol

ates

, hum

ans,

mos

quit

oes)

.

Chem

othe

rapy

In v

itro

met

hods

, ani

mal

mod

els,

SNP

for r

esis

tanc

e.

Diag

nosi

sRa

pid

assa

y fo

r G6P

D de

ficie

ncy,

ass

ay fo

r dru

g le

vels

.

Para

site

/hos

t/ve

ctor

Infe

ctio

n dy

nam

ics,

met

abol

ic in

tera

ctio

ns, d

efen

se m

echa

nism

s.

Inse

ctic

ides

Fiel

d te

st t

o as

sess

inse

ctic

ide-

trea

tmen

t st

atus

of b

edne

ts.

Tran

sgen

ics

Gene

s in

to p

opul

atio

ns a

nd g

ene

flow.

Path

ogen

esis

Spec

ies

inte

ract

ion,

Pla

smod

ium

–HIV

–TB

etc.

Tran

sgen

ics

Cryo

pres

erva

tion

of m

osqu

itoe

s.

Path

ogen

esis

P. v

ivax

pat

hoph

ysio

logy

, ide

ntifi

cati

on o

f viru

lenc

e fa

ctor

s.

Popu

lati

on b

iolo

gyVe

ctor

, tra

nsm

issi

on d

ynam

ics.

Vacc

ines

Deliv

ery

syst

ems.


Mal

aria

CURRENT STATUS

It is widely recognized that sociocultural envi-ronment plays a significant role in the epidemi-ology of malaria and that the success of malaria control initiatives depends on serious attention to social, political, economic and equity issues. Within the social sciences, there is now a con-siderable body of literature related to malar-ia. In 1978, WHO published A bibliography on the behavioural, social and economic aspects of malaria and its control 3. A monograph summa-rizing some of the pertinent social science lit-erature published in the last two decades, The behavioural and social aspects of malaria and its control – an introduction and annotated bib-liography 4, was published by TDR in 2003. Also of note is the establishment, in 2001, of the Partnership for Social Sciences in Malaria Control (PSSMC), based at the London School of Hygiene and Tropical Medicine and Centers for Disease Control and Prevention, Atlanta, and its Clearinghouse for Social Science and Malaria Literature.

The inter-relationship between malaria and behavioural and sociocultural (including social, economic, political, cultural and equity) factors still needs to be re-emphasized and made a cen-tral part of strategies for the control of malaria (not just an afterthought). It should be under-scored that, just as in the biosciences, the health-related social sciences include a number of disciplines (among others, medical anthropolo-gy, health economics, medical sociology, health psychology, social epidemiology, health poli-cy, medical geography), each with its unique approach and particular strengths. While addi-

tional research in the social sciences is needed, it should be recognized that a great deal of progress could be made by using available knowledge from the social sciences in combination with that from the biosciences.

RECOMMENDATIONS FOR FUTURE RESEARCH

The following should be considered areas of social research of high priority. Areas that the Working Group considered to be of high priori-ty for TDR and/or partners are listed in the table below.

Vulnerability and coping strategies

The populations that are at the greatest risk of malaria are often poor and marginalized. Little is known about coping strategies of these pop-ulations in the context of other risks and prior-ities faced by households/individuals trying to maximize welfare. Although recent microeco-nomic research has shed some light on the bur-den of malaria at the household level, a number of important questions remain unanswered, for example, there is a dichotomy between the results generated by macroeconomic and micro-economic studies regarding the burden of malar-ia. Anthropological and sociological research will help to further elucidate understanding of the rel-ative social and economic value placed on the burden of malaria.

Key research questions:– What are current malaria-related coping strate-

gies?

– How does malaria “rank” in relation to other

5. Social, economic, behavioural, health systems and policy research for the treatment and prevention of malaria

3 Sotiroff-Junker, J (1978). A bibliography on the behavioural, social and economic aspects of malaria and its control. Geneva, World Health Organization (WHO offset publication No. 42).4 Heggenhougen HK, Hackethal V & Vivek P (2003). The behavioural and social aspects of malaria and its control. An introduction and annotated bibliography. Geneva, Special Programme for Research and Training in Tropical Diseases (TDR/STR/SEB/VOL/03.1).


Mal

aria

perceived and actual risks faced by households and individuals?

– How can vulnerability be reduced and commu-nity resilience be bolstered?

Equity: development and application of a common methodology for measuring socioeconomic status and more qualita-tive descriptors of poverty and equity

The SWG suggested that this area of research should be of high priority for TDR in collabora-tion with Demographic Health Surveys (DHS), the World Bank and others. In order to evaluate progress made in providing the poorest popula-tions with interventions for the control of malar-ia, it is necessary that poverty be measured in a standardized and relatively simple manner. In economics, there are some possible methods by which poverty can be measured (e.g. the asset index approach); however, no consensus has been reached on a common methodology, thus inhibiting comparability of results. Moreover, such methods only include quantifiable estimates of poverty and neglect other equally important dimensions, such as gender, ethnicity, social sta-tus, nutritional status and educational attainment.

Key research topics:– Development and validation of a common

methodology for quantitative measurement of poverty;

– Development of an interrelated matrix of key qualitative indicators of poverty;

– Development of guidelines for the juxtaposi-tion of the qualitative and quantitative indica-tors of poverty;

– Application of these tools in order to further examine vulnerability to malaria by socioe-conomic stratum, gender, ethnicity and other determinants of inequality.

Gender and malaria

Gender roles and responsibilities can have a far-reaching impact on patterns of malaria and the effectiveness of prevention and control efforts. Gender roles can also have a powerful influ-ence on the way in which health-care services are delivered, how health-care providers perceive their clients, and ultimately the degree to which health-care services respond effectively to the clients’ needs. Gender-related barriers to malaria care may vary greatly in diverse settings, calling for context-specific basic and operational social research.

Key research questions:– On the basis of age- and sex-disaggregated

data from past surveys and studies, what is the magnitude and nature of gender disparities?

– What are the gender-related problems of access to and care within malaria prevention and treatment programmes?

– How can existing evidence from social research on differential access to malaria-relat-ed information, prevention and therapy be translated into appropriate gender-sensitive interventions?

Improving prevention: comparative multi-disciplinary social research evaluating interventions to scale up and target the distribution of ITNs

Evidence on the relative performance of the pub-lic and private sectors in distributing ITNs (e.g. free delivery by the public sector versus paid delivery by the private sector) is patchy and much disputed. Moreover, there are no data on the performance of these strategies on a large scale. In addition, large-scale targeting strategies such as voucher schemes, currently being funded by the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM), require high-quality mon-


Mal

aria

itoring and evaluation in order to document and learn from their successes and failures. An under-standing of the incentives and influences operat-ing on suppliers in the private sector of tools for prevention (especially ITNs) is vital if the private sector is to be engaged fully in initiatives such as large-scale voucher schemes.

Key research questions:– For each ITN delivery strategy, evidence regard-

ing equity, efficiency and sustainability issues in an operational setting should be document-ed. Multi-disciplinary economic, sociological and anthropological research will be required to quantify and describe these parameters.

– Novel approaches to targeting ITNs to specif-ic groups (e.g. vouchers, subsidies [including 100%], market segmentation, social marketing) must be evaluated carefully in order to docu-ment and learn from successes and failures.

– Research is required into identification of incentives and motivations (positive and nega-tive) for the private- and public-sector suppliers of ITN products (especially at lower levels of the distribution chain, i.e. retailers and clinics).

Improving treatment: supply-side research on the private sector

It is now recognized that the private sector pro-vides a high proportion of all treatment (and tools for prevention) of malaria. If access to and quality of treatment are to be improved, it is crit-ical to understand the contributions and limita-tions of the private sector; this will also facilitate engagement with the private sector in order to improve overall treatment of malaria. Little is currently known about the incentives, attitudes, practices, quality and performance of treatment providers in the private sector (informal and for-mal, including traditional healers and tradition-al birth attendants), or how these compare with those in the public sector.

Key research topics:– A comparison of the quality (measured in var-

ious ways, with particular attention paid to patients’ perceptions of quality) of different types of public and private service provider, to enable identification of the relative strengths and weaknesses of each type of service provider;

– Detailed benefit–incidence analysis to identify equity in access to each type of service provid-er (e.g. access and uptake, by socioeconom-ic status);

– Operational research into identifying mecha-nisms to develop and strengthen partnerships with traditional healers and traditional birth attendants.

Health sector reform and control of malaria

Previous research supported by TDR reveals that health sector reforms have unwanted side-effects and many do not achieve their intended effect. Often this is because the decision-base was too weak, i.e. not enough was known about the con-text and functioning of the system that was to be changed/reformed. Research has a role to play both in providing a more solid initial foundation of knowledge on which decisions can be based, and in evaluating the effects of reforms as they proceed, in particular, effects on vulnerable and marginal populations.

Key research questions:– What is the impact of health sector reforms on

malaria, particularly with respect to the inte-gration of vertical efforts to control malaria into horizontal systems?

– Can mechanisms to enhance involvement in malaria-related activities at the district level be identified?

– What are the implications of changing health-care service delivery systems for malaria-relat-


Mal

aria

ed health-care service use patterns, particularly with respect to equity of access?

– What is the impact of vertical programming on organizational behaviour, incentives and priori-ty-setting at the district level?

Public–private partnerships: policy and operational research on impact, viabil-ity, sustainability and optimal balance

There is increasing recognition of the role of public–private partnerships in the delivery of interventions for malaria and a broader range of health-care interventions. However, little is known about the impact, viability, sustainability and optimal balance in such partnerships. There is a need to develop an evidence base to deter-mine elements of public–private partnerships that are or are not effective, in order to ensure their future success.

Key research areas:– Health systems and implementation research to

describe successful models for public–private partnerships in various settings to ensure con-tinued availability of antimalarials;

– Health systems and operational research to identify mechanisms for integration of drug donation programmes into the large-scale implementation of malaria control pro-grammes;

– Policy analysis to identify and document the relative roles played by the private and pub-lic sectors in (the scaling up of) ITN delivery strategies.

Policy, economic and social analysis: understanding the process of change in malaria control

The process of policy change is becoming a more important aspect of malaria control as a result of more frequent changes in drug policy (due to

drug resistance), changes in national policy con-cerning ITNs, tax and tariff reform on ITN mate-rials and changes in insecticides used in public health for the control of malaria (e.g. the shift to DDT). There is a need to document the proc-ess and costs (economic and social) to govern-ments of policy change, including identifying the processes, actors, content and context of policy change and implementation.

Key research areas:– Cross-country policy analysis to understand

the process of change, prerequisites of success, and barriers to the control of malaria, with regard to changes in drug and ITN policies;

– Economic costing of the process of drug-policy change – this should be considered in addition to direct costs (i.e. cost of new drugs) by gov-ernments considering changing drug policy.

Ethical, legal and social issues of new malaria-related tools

The development and large-scale use of new biotechnologies in the field of malaria gener-ate a number of ethical issues and have legal and social implications; public awareness, acceptabil-ity and adherence are prerequisites for the effec-tiveness and utility of these technologies.

Key research questions:– How is/will the use/future use of specific

malaria-related tools be affected by public per-ception and acceptability?

– What are the ethical, legal and social issues (ELSI) associated with new tools and their development (e.g. vaccine trials)?

Persistence, emergence and resurgence of malaria

There is a gap in knowledge of the large-scale social and bio-ecological dynamics that deter-


Mal

aria

mine why, in many countries, malaria per-sists and re-emerges. Rapid social, economic and political change may be decisive contribut-ing factors in the persistence and resurgence of malaria. Upstream social research and research combining social and biological/ecological fac-tors (“eco-bio-social research”) on the impact of rapid social, political and economic change, glo-balization, and the widening of social inequali-ties on the persistence, emergence and resurgence of infectious diseases, could shed light on health policy options in a rapidly globalizing world.

Key research questions:– How do large-scale economic processes and

policies (e.g. trade agreements, globalization) affect the production and availability of effec-tive drugs, diagnostics and vaccines for malaria?

– How does globalization affect social and health policies and contribute to social inequal-ities, with repercussions in health-care systems and services related to malaria?

– What are the human factors contributing to the emergence of drug and insecticide resistance (e.g. self medication, polypharmacy, agricul-tural use of insecticides)?

– What are the links between environmental, social and biological forces in the epidemiol-ogy of malaria (e.g. forest clearing, poverty-induced migration, El Niño)?

Social science inputs permeate many of the research priorities listed above, especially in the general area of implementation research.


Hig

hpr

iori

ty

Rese

arch

for

whi

ch T

DR h

as a

com

para

tive

adv

anta

geAc

tivi

ties

mos

t ap

prop

riat

e fo

r ot

her

part

ners

Vuln

erab

ility

and

cop

ing

stra

tegi

esSt

udie

s to

cap

ture

impa

ct o

f cop

ing

stra

tegi

es in

resp

onse

to

risk

of d

isea

se in

the

con

text

of

oth

er ri

sks

and

prio

ritie

s fa

ced

by h

ouse

hold

s/in

divi

dual

s tr

ying

to

max

imiz

e w

elfa

re.

Ineq

uity

Rese

arch

exa

min

ing

vuln

erab

ility

to

mal

aria

by

soci

oeco

nom

ic s

trat

a,

gend

er, e

thni

city

and

oth

er d

eter

min

ants

of i

nequ

alit

y.

Pers

iste

nce,

em

erge

nce

and

resu

rgen

ce o

f m

alar

iaBa

sic

soci

al re

sear

ch o

n th

e im

pact

of g

loba

lizat

ion

and

wid

enin

g so

cial

ineq

ualit

ies

on t

he e

pide

mio

logy

of m

alar

ia.

Hea

lth

polic

yCr

oss-

coun

try

polic

y an

alys

is t

o un

ders

tand

the

pro

cess

of

chan

ge, p

rere

quis

ites

to

succ

ess,

and

bar

riers

to

mal

aria

co

ntro

l (e.

g. d

rug

polic

y ch

ange

, ITN

pol

icy)

.

Ineq

uity

Deve

lopi

ng a

nd v

alid

atin

g a

com

mon

met

hodo

logy

for m

easu

ring

soci

oeco

nom

ic s

tatu

s an

d m

ore

qual

itat

ive

desc

ripto

rs o

f pov

erty

and

eq

uity

. A re

-ana

lysi

s of

exi

stin

g da

ta s

ets

to g

ain

furt

her u

nder

stan

ding

of

rela

tion

ship

bet

wee

n so

cioe

cono

mic

sta

tus

and

mal

aria

wou

ld b

e us

eful

.

Med

ium

pr

iori

tyDe

man

d fo

r m

alar

ia t

reat

men

tEc

onom

etric

ana

lysi

s of

(ex

isti

ng a

nd n

ew)

larg

e ho

useh

old

surv

eys

to p

redi

ct e

ffec

t of

eco

nom

ic,

soci

al a

nd c

ultu

ral f

acto

rs o

n he

alth

-car

e ch

oice

s (w

hen,

whe

re, w

ho a

nd h

ow t

reat

men

t is

so

ught

) an

d to

mea

sure

resp

onsi

vene

ss o

f dem

and

to c

hang

es in

the

se a

nd o

ther

fact

ors.

Burd

en o

f m

alar

ia•

Basi

c so

cial

rese

arch

on

the

soci

al b

urde

n an

d im

pact

of m

alar

ia —

incl

udin

g an

und

erst

andi

ng o

f the

mec

hani

sms

by w

hich

mal

aria

aff

ects

hou

seho

lds,

co

mm

unit

ies

and

econ

omie

s (d

iffer

enti

ated

by

leve

l of t

rans

mis

sion

).•

Sect

or-s

peci

fic c

ase

stud

ies

on t

he b

urde

n of

mal

aria

(to

uris

m, m

inin

g, a

gric

ultu

re

etc.

) —

gre

at p

oten

tial

for p

rivat

e-pu

blic

par

tner

ship

s in

rese

arch

and

con

trol

.

Eco-

bio-

soci

al r

esea

rch

Eluc

idat

ing

the

links

bet

wee

n en

viro

nmen

tal,

soci

al a

nd b

iolo

gica

l for

ces

in t

he

epid

emio

logy

of m

alar

ia (

e.g.

fore

st c

lear

ing,

pov

erty

-ind

uced

mig

rati

on, E

l Niñ

o).

Com

plex

em

erge

ncie

s•

Basi

c re

sear

ch t

o el

ucid

ate

soci

al, p

olit

ical

and

eco

nom

ic li

nks

betw

een

conf

lict,

pop

ulat

ion

mov

emen

t an

d ot

her f

orm

s of

com

plex

em

erge

ncie

s (n

atur

al d

isas

ters

, clim

ate

anom

alie

s) a

nd m

alar

ia.

• Ap

plie

d re

sear

ch in

to a

ppro

pria

te a

nd e

ffec

tive

inte

rven

tion

s in

com

plex

em

erge

ncy

situ

atio

ns.

Polic

y an

alys

is o

f he

alth

sec

tor r

efor

m a

nd it

s im

pact

on

mal

aria

con

trol

.

Dise

ase

burd

enSt

udie

s us

ed in

con

junc

tion

wit

h ex

isti

ng c

ost-

effe

ctiv

enes

s an

alys

es t

o id

enti

fy t

hose

inte

rven

tion

s w

hich

wou

ld h

ave

the

bigg

est

impa

ct, e

spec

ially

am

ong

poor

est.

Expa

nd t

he s

cope

of m

orbi

dity

and

mor

talit

y ou

tcom

e in

dica

tors

incl

uded

in b

urde

n of

dis

ease

est

imat

es t

o in

clud

e se

vere

mal

aria

, seq

uela

e, a

naem

ia, l

ow b

irthw

eigh

t.

Tabl

e 4.

SW

G pr

iori

tiza

tion

of n

eede

d re

sear

ch in

soc

ial,

econ

omic

, beh

avio

ural

, hea

lth

syst

ems

and

polic

y as

pect

s of

the

tre

atm

ent

and

prev

enti

on o

f mal

aria


Mal

aria

Hig

hpr

iori

ty

Rese

arch

for

whi

ch T

DR h

as a

com

para

tive

adv

anta

geAc

tivi

ties

mos

t ap

prop

riat

e fo

r ot

her

part

ners

Vuln

erab

ility

and

cop

ing

stra

tegi

esSt

udie

s to

cap

ture

impa

ct o

f cop

ing

stra

tegi

es in

resp

onse

to

risk

of d

isea

se in

the

con

text

of

oth

er ri

sks

and

prio

ritie

s fa

ced

by h

ouse

hold

s/in

divi

dual

s tr

ying

to

max

imiz

e w

elfa

re.

Ineq

uity

Rese

arch

exa

min

ing

vuln

erab

ility

to

mal

aria

by

soci

oeco

nom

ic s

trat

a,

gend

er, e

thni

city

and

oth

er d

eter

min

ants

of i

nequ

alit

y.

Pers

iste

nce,

em

erge

nce

and

resu

rgen

ce o

f m

alar

iaBa

sic

soci

al re

sear

ch o

n th

e im

pact

of g

loba

lizat

ion

and

wid

enin

g so

cial

ineq

ualit

ies

on t

he e

pide

mio

logy

of m

alar

ia.

Hea

lth

polic

yCr

oss-

coun

try

polic

y an

alys

is t

o un

ders

tand

the

pro

cess

of

chan

ge, p

rere

quis

ites

to

succ

ess,

and

bar

riers

to

mal

aria

co

ntro

l (e.

g. d

rug

polic

y ch

ange

, ITN

pol

icy)

.

Ineq

uity

Deve

lopi

ng a

nd v

alid

atin

g a

com

mon

met

hodo

logy

for m

easu

ring

soci

oeco

nom

ic s

tatu

s an

d m

ore

qual

itat

ive

desc

ripto

rs o

f pov

erty

and

eq

uity

. A re

-ana

lysi

s of

exi

stin

g da

ta s

ets

to g

ain

furt

her u

nder

stan

ding

of

rela

tion

ship

bet

wee

n so

cioe

cono

mic

sta

tus

and

mal

aria

wou

ld b

e us

eful

.

Med

ium

pr

iori

tyDe

man

d fo

r m

alar

ia t

reat

men

tEc

onom

etric

ana

lysi

s of

(ex

isti

ng a

nd n

ew)

larg

e ho

useh

old

surv

eys

to p

redi

ct e

ffec

t of

eco

nom

ic,

soci

al a

nd c

ultu

ral f

acto

rs o

n he

alth

-car

e ch

oice

s (w

hen,

whe

re, w

ho a

nd h

ow t

reat

men

t is

so

ught

) an

d to

mea

sure

resp

onsi

vene

ss o

f dem

and

to c

hang

es in

the

se a

nd o

ther

fact

ors.

Burd

en o

f m

alar

ia•

Basi

c so

cial

rese

arch

on

the

soci

al b

urde

n an

d im

pact

of m

alar

ia —

incl

udin

g an

und

erst

andi

ng o

f the

mec

hani

sms

by w

hich

mal

aria

aff

ects

hou

seho

lds,

co

mm

unit

ies

and

econ

omie

s (d

iffer

enti

ated

by

leve

l of t

rans

mis

sion

).•

Sect

or-s

peci

fic c

ase

stud

ies

on t

he b

urde

n of

mal

aria

(to

uris

m, m

inin

g, a

gric

ultu

re

etc.

) —

gre

at p

oten

tial

for p

rivat

e-pu

blic

par

tner

ship

s in

rese

arch

and

con

trol

.

Eco-

bio-

soci

al r

esea

rch

Eluc

idat

ing

the

links

bet

wee

n en

viro

nmen

tal,

soci

al a

nd b

iolo

gica

l for

ces

in t

he

epid

emio

logy

of m

alar

ia (

e.g.

fore

st c

lear

ing,

pov

erty

-ind

uced

mig

rati

on, E

l Niñ

o).

Com

plex

em

erge

ncie

s•

Basi

c re

sear

ch t

o el

ucid

ate

soci

al, p

olit

ical

and

eco

nom

ic li

nks

betw

een

conf

lict,

pop

ulat

ion

mov

emen

t an

d ot

her f

orm

s of

com

plex

em

erge

ncie

s (n

atur

al d

isas

ters

, clim

ate

anom

alie

s) a

nd m

alar

ia.

• Ap

plie

d re

sear

ch in

to a

ppro

pria

te a

nd e

ffec

tive

inte

rven

tion

s in

com

plex

em

erge

ncy

situ

atio

ns.

Polic

y an

alys

is o

f he

alth

sec

tor r

efor

m a

nd it

s im

pact

on

mal

aria

con

trol

.

Dise

ase

burd

enSt

udie

s us

ed in

con

junc

tion

wit

h ex

isti

ng c

ost-

effe

ctiv

enes

s an

alys

es t

o id

enti

fy t

hose

inte

rven

tion

s w

hich

wou

ld h

ave

the

bigg

est

impa

ct, e

spec

ially

am

ong

poor

est.

Expa

nd t

he s

cope

of m

orbi

dity

and

mor

talit

y ou

tcom

e in

dica

tors

incl

uded

in b

urde

n of

dis

ease

est

imat

es t

o in

clud

e se

vere

mal

aria

, seq

uela

e, a

naem

ia, l

ow b

irthw

eigh

t.

6. Capacity and partnership building

The recommendations presented below were compiled from those made by each of the four Working Groups.

Capacity building requirements in malar-ia research are broad and challenging. TDR has an outstanding record in training and supporting young researchers from countries where malar-ia is endemic and this important role needs to be expanded. However, it will be insufficient mere-ly to train scientists from developing countries in the necessary skills: attention will need to be paid to arrangements for career development and provision of a satisfactory working environ-ment. Support should be provided for Internet connection, computational capability, collab-orations between developed and developing countries and between developing countries, net-working opportunities, technology transfer and sharing of reagents. Opportunities for the devel-opment of infrastructure related to new technolo-gies should be offered in association with support for research projects.

In view of TDR’s international malaria research agenda, the SWG considered that development of the following areas was especially important:

Clinical investigation and trials capacity building

There is a need for investment in both facili-ties and trained personnel. This activity would be best conducted in cooperation with existing and future funders of clinical trial sites. Capacity development is needed for good clinical and good laboratory practices, trial analysis and clini-cal pharmacology.

Drug analytical facilities

Capacity in drug analytical methods is current-ly inadequate, thus training and improved facili-ties are needed.

Statistical analysis

The analysis and interpretation of epidemiologi-cal and therapeutic studies still relies heavily on the expertise of statisticians from industrialized countries. This deficiency needs to be addressed.

Operational research, evaluation of interventions and health care systems

Much more expertise is required in this area, in view of the increased agenda for implementa-tion research. Expertise is lacking, particularly in public health, health economics, field epide-miology, entomology, bio-ethics and toxicology (including pharmacovigilance). Opportunities for placements to perform applied research in large-scale control operations (for example in the form of fellowships) should be created.

Bioinformatics

Training in bioinformatics is of a high priori-ty, in order to make effective use of the wealth of data generated by the recent completion of the sequencing of the malaria parasite, human and mosquito genomes and to analyse these data to identify potential tools for understanding of host–parasite interactions and identification of targets for drugs, vaccines, diagnostics, insecticides and genetic manipulation of vectors.

Functional genomics

Research into parasite and vector target dis-covery requires training in functional genom-ics, including new molecular techniques such as transfection, gene knockouts, population genetic analysis, proteomics, microarray analysis, com-parative species genomics and modelling.

Product development

The development of drugs and insecticides requires training and technology transfer in toxi-


Mal

aria

cology, pharmacology, structural biology, rational molecular design, combinatorial chemistry, and high-throughput screening. Capacity building in good laboratory practice (GLP) is needed for pre-clinical development.

Social sciences

There is a strong need for the strengthening of postgraduate training in social sciences research

with a focus on health, and the integration of social sciences into biomedical training pro-grammes on malaria.

Finally, TDR should implement the research capability strengthening (RCS) strategy to track and evaluate the outcomes of training and capaci-ty building activities.


Mal

aria

Annex 1 AGENDA: Scientific Working Group on Malaria


Day 1 (Monday 24 March)

Time Item Speaker

09:00–09:30 Welcome address Dr D. Heymann, Ex Director CDSDr C. Morel, Director, TDRDr F. Traore-Nafo, Ex. Sec. RBM

09:30–09:45 TDR disease strategic plan Dr J. Lazdins, TDR

09:45–10:00 Meeting objectives and process Dr Y. Touré, TDR

10:00–10:30 Current strategic emphases for malaria control in RBM Dr D. Alnwick, Director, MAL (20 min + 10 min discussion)

10:30–11:00 Coffee

11:00–11:30 Current strategic emphases for malaria research in TDR Dr Y. Touré(20 min + 10 min discussion)

Improved tools and strategies for the treatment of malaria

11:30–12:00 Improved access to treatment and use of antimalarials Dr D. Broun(20 min + 10 min discussion)

12:00- 12:30 Improved management of malaria in children Dr Mark W. Young (20 min + 10 min discussion)

12:30–14:00 Lunch

14:00–14:30 Improved management of malaria during pregnancy Dr F. Ter Kuile(20 min + 10 min discussion)

14:30–15:00 New and improved antimalarial drugs and therapeutic strategies Dr S. Looareesuwan(20 min + 10 min discussion)

Improved tools and strategies for the prevention of malaria

15:00–15:30 Strategies for scaling up distribution of insecticide treated nets Dr J. Lines(20 min + 10 min discussion)

15:30–16:00 Coffee

16:00–16:30 Research strategies for improving vector control and insecticide resistance monitoring and management

Dr C. Curtis (20 min + 10 min)

16:30–17:00 Strategies for scaling up intermittent preventive treatment for malaria and anaemia during pregnancy and in children

Dr C. Menendez(20 min + 10 min)

17:00–17:30 Improved methods of surveillance and information management (including to monitor and predict antimalarial drug resistance, to assess preparedness for epidemics)

Dr A. Djimdé(20 min + 10 min)

17:30–18:00 Strategies for improved malaria diagnostics (including rapid diagnosis)

Dr J. Barnwell(20 min + 10 min)


Day 2 (Tuesday 25 March)

Time Item Speaker

09:00–09:30 Strategies to assess impact of new interventions Dr F. Binka(20 min + 10 min)

Innovative approaches to the treatment and prevention of malaria

09:30–10:00 Genomes for novel targets for drugs, diagnosis and vaccine Dr D. Wirth(20 min + 10 min)

10:00–10:30 Prospective on drug discovery and development Dr S. Nwaka (20 min + 10 min)

10:30–11:00 Coffee

11:00-11:30 Prospective on malaria vaccine discovery and development Dr C. Chitnis(20 min + 10 min)

11:30–12:00 Prospective on strategies for interrupting malaria transmission Dr M. Jacobs-Lorena(20 min + 10 min)

12:00–12:30 New advances in insecticide development Dr H. Ranson (20 min + 10 min)

12:30–14:00 Lunch

Social, economic, behavioural, health systems and policy research for the treatment and prevention of malaria

14:00–14:30 Social, cultural and behavioural issues of malaria treatment and prevention

Dr H. Mwenesi(20 min + 10 min)

14:30–15:00 Social, political and economic issues related to malaria resurgence and inequalities of access to treatment and prevention of malaria

Dr H.K. Heggenhougen(20 min + 10 min)

15:00–15:30 Economics of malaria and its control (including economic impact of malaria, cost–effectiveness of interventions, health system and malaria control issues

Dr E. Worrall (20 min + 10 min)

15:30–15:40 Introduction of working group strategy Dr Y Touré (10 min)

15:40–16:00 Coffee

16:00–18:00 Working Groups I, II, III, IV

Day 3 (Wednesday 26 March)

Time Item Speaker

08:30–10:30 Working Groups (continued)

10:30–11:00 Coffee

11:00–12:30 Working Groups (continued)

12:30–14:00 Lunch

14:00–14:40 Plenary report, working group I Working Group Rapporteur (20 min + 20 min)

14:40–15:20 Plenary report, working group II Working Group Rapporteur(20 min + 20 min)

15:20–16:00 Coffee

16:00–16:40 Plenary report, working group III Working Group Rapporteur (20 min + 20 min)

16:40–17:20 Plenary report, working group IV Working Group Rapporteur (20 min + 20 min)


Day 4 (Thursday, 27 March)

Time Item Speaker

08:30–10:30 Small group to review the overall prioritization and harmonize the recommendations

Small group: SWG Chair and Rapporteurs , TDR functional areas’ coordinators

Working Groups to finalize their reports Working Groups

Plenary rapporteurs to finalize the SWG meeting draft report SWG Chair/Rapporteurs

10:30–11:00 Coffee

11:00–12:30 Plenary rapporteurs to draft the SWG meeting report; Draft report distributed to the meeting participants for discussion in plenary

SWG Chair/Rapporteurs

12:30–14:00 Lunch

14:00–15:30 Small group reports to the plenary session;Plenary presentation, discussion and amendment of the SWG draft report

All

15:30–16:00 Coffee

16:00–16:30 Continuation of discussion and amendment of the draft SWG reportAny other business

16:30–17:30 Concluding remarks Dr D.F. Wirth (Chair)Dr D. Alnwick, RBMDr C. Morel, TDR

Day 5 (Friday 28 March)

Time Item Speaker

09:00–10:30 Finalization of the SWG Report Chair, Rapporteurs

10:30–11:00 Coffee


12:30–14:00 Lunch


15:30–16:00 Coffee



Mal

aria

Annex 2 LIST OF PARTICIPANTS: Scientific Working Group on Malaria


*Dr Myriam Arevalo-Herrera, Universidad del Valle, Faculdad de Salud, Fundacion Centro de Primates, PO Box Apartado 2188, Cali, Columbia. Tel.: +57 2 558 1931 or 1946 Fax: +57 2 557 0449 E-mail: [email protected]

*Dr John W. Barnwell, Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, MS-F36, Building 22B, 477 Buford Highway, NE, Atlanta, Georgia 30341, USA. Tel.: +1 (770) 488 4528/4969 Fax: +1 (770) 488 4253 E-mail: [email protected]

*Dr Fred Binka, School of Public Health, University of Ghana, Legon, Ghana. Tel.: +233 308 131 031 Fax: +233 21 500 388 401 550 E-mail: [email protected]/[email protected]

Dr Anders Bjorkman, Karolinska Hospital, Department of Medicine, Division of Infectious Diseases, S-17176, Stockholm, Sweden. Tel.: +46 851 771 866 Fax: +46 851 771 806 E-mail: [email protected]

*Dr Dennis Broun, MSH, Immeuble Keynes, 13, Chemin du Levant, 01210 Ferney-Voltaire, France. Tel.: +33 450 409 289 Fax: +33 450 504 298 E-mail: [email protected]

*Dr Chetan Chitnis, International Centre for Genetic Engineering and Biotechnology, P. O. Box 10504, Aruna Asaf Ali Marg, New Delhi 110067, India. Tel.: +91 11 618 7695 or 686 7357 Fax: +91 11 616 2316 E-mail: [email protected]

Professor Chris Curtis, Vector Control in Mosquito Genetics, London School of Hygiene and Tropical Medicine, Department of Infectious and Tropical Diseases, University of London, Keppel Street, London WC1E 7HT, United Kingdom. Tel.: +44 207 927 2339 E-mail: [email protected]

Dr Abdoulaye Djimdé, Faculté de médecine de pharmacie et d’odontostomatologie, PO Box 1805, Point G, Bamako, Mali, West Africa. Tel.: +223 222 8109 Fax: +223 222 8109 E-mail: [email protected]

Professor Brian M. Greenwood, Department of Medical Parasitology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom. Tel.: +44 171 927 2348/636 8636 Fax: +44 171 636 8739 E-mail: [email protected]

Dr Harald Kristian Heggenhougen, Department of International Health, Boston University School of Public Health, 715 Albany Street, T4W, Boston, MA 02118, USA. Tel.: +1 (617) 414 1450 Fax: +1 (617) 638 4476 E-mail: [email protected]

Dr Marcelo Jacobs-Lorena, Case Western Reserve University, School of Medicine, BRB 631, Department of Genetics, 10900 Euclid Avenue, Cleveland, Ohio 44106-4955, USA. Tel.: +1 (216) 368 2791; +1 (216) 368 2791/2790 Fax: +1 (216) 368 3432 E-mail: [email protected]

Dr Christian Lengeler (Rapporteur), Swiss Tropical Institute, PO Box 4002, Basel, Switzerland/Current address: 10/2 McPherson Road, Cooke Town, Bangalore 560005, India. Tel.: +91 98 453 68 571 E-mail: [email protected]

Dr Jonathan Lines, London School of Hygiene and Tropical Medicine, Department of Medical Parasitology, Keppel Street, London WC1E 7HT, United Kingdom. Tel.: +44 171 636 8636 Fax: +44 171 636 8739 E-mail: [email protected]

*Dr Sornchai Looareesuwan, Mahidol University, Faculty of Tropical Medicine, Hospital for Tropical Diseases, 420/6 Rajvithi Road, Code Postal 10400, Bangkok, Thailand. Tel.: +662 247 1688 Fax: +662 245 7288 E-mail: [email protected]

Temporary Advisers

(* unable to attend)


Professor Kevin Marsh (Rapporteur), Kenya Medical Research Institute (KEMRI), Wellcome Trust Collaborative Programme, PO Box 230, Bofa Road, Kilifi, Kenya. Tel.: +254 1252 2063 Fax: +254 1252 2390 E-mail: [email protected]

Dr Wilfred F. Mbacham, University of Yaounde, Faculty of Science, Biotechnology Center. PO Box 812, Yaounde, Cameroon. Tel.: +237 231 2880 Fax: +237 231 2880

Dr Clara Menendez, Centro de Salud Internacional, Unidad de Epidemiologia y Bioestadistica Hospital Clinic, Villaroel 170, Barcelona 08036, Spain. Tel.: +34 93 227 5706 Fax: +34 93 451 5272 E-mail: [email protected]

*Dr David Modiano, Dipartimento di Scienze di Sanità Pubblica, Sezione di Parassitologia Università “La Sapienza”, P. le Aldo Moro 5, 00185, Rome, Italy. Tel.: +39 06 4455 780 Fax: +39 06 4991 4653 E-mail: [email protected]

*Dr Hassan Mshinda, Director, Ifakara Health Research and Development Centre, PO Box 78373, Dar es Salaam, United Republic of Tanzania. Tel.: +255 22 212 1956; Mobile: +255 22 742 782210 Fax: +255 22 213 0660 E-mail: [email protected]

*Dr Halima Abdullah Mwenesi, Regional Research Coordinator, NetMark Africa Regional Malaria Program, 31B Monte Carlo Crescent, Kyalami Business Park, Midrand 1684, South Africa. Tel.: +27 114 660 238 Fax: +27 114 660 579 E-mail: [email protected]

Dr Francine Ntoumi, Hopital Albert Schweitzer, Laboratoires de Recherche. BP 118, Lambarene, Gabon. Tel.: +241 58 10 99 Fax: +241 58 11 96 E-mail: [email protected]

Dr Solomon Nwaka, Medicines for Malaria Venture, International Centre Cointrin, Block G, 3rd Floor, Route de Pré-Bois 20, PO Box 1826, CH-1215 Geneva 15, Switzerland. Tel.: +41 22 799 4065 Fax: +41 22 799 4061 E-mail: [email protected]

Dr Luiz H. Pereira da Silva, State Secretariat of Health, Centro de Pesquisa em Medicina Tropical, PO Box CP 87 Correio Central, Porto Velho RO, Brazil. Tel.: +55 69 225 3304 Fax: +55 69 225 3304 E-mail: [email protected]

Dr Hilary Ranson, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, United Kingdom. Tel.: +44 151 705 3281 E-mail: [email protected]

*Dr Mario Henry Rodriguez, Centro de Investigaciones sobre Enfermedades Infecciosas Instituto Nacional de Salud Publica, Av. Universidad No. 655, Cuernavaca, Morelos, 62508, Mexico. Tel.: +73 138 969 Fax: +73 175 485 E-mail: [email protected]

Dr Massambou Sacko, Programme National de Lutte Contre le Paludisme Division de la Prévention et de la Lutte contre la Maladie (DPLM), Direction Nationale de la Santé Publique, BP 232, Bamako, Mali. Tel.: +223 220 3306/220 3697 Fax: +223 220 3673 E-mail: [email protected] ; [email protected]

*Dr Sarala K. Subbarao, Indian Council of Medical Research, Malaria Research Centre, 22 Sham Nath Marg, New Delhi 110054, India. Tel.: +91 113 981 690 Fax: +91 113 946 150 E-mail: [email protected]

*Dr Marcel Tanner, Swiss Tropical Institute, Department of Public Health and Epidemiology, Socinstrasse 57, PO Box 4002, Basel, Switzerland. Tel.: +41 612 84 8 111/8283 Fax: +41 61 271 7951/8654 E-mail: [email protected]

Dr Feiko O. ter Kuile, Centers for Disease Control, Division of Parasitic Diseases, Malaria Epidemiology Branch, Mailstop F-22, Atlanta, GA 30333, USA. Tel.: +1 770 488 7760 Fax: +1 770 488 7761 E-mail: [email protected]

Dr Jean-François Trape, Institut de Recherche pour le Développement (IRD), U.R. Paludologie Afrotropicale. BP 1386, Dakar, Senegal. Tel.: +221 849 3582/+221 849 3584 Fax: +221 832 4307 E-mail: [email protected]


Dr Nicholas J. White, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand. Tel.: +662 2460.832 Fax: +662 246.7795 E-mail: [email protected]

Dr Peter A. Winstanley, University of Liverpool, Department of Pharmacology and Therapeutics. PO Box 147, Ashton Street, Liverpool L69 3BX, United Kingdom. Tel.: +44 151 722 2710 Fax: +44 151 794 5540 or 4222 E-mail: [email protected]

Professor Dyann F. Wirth (Chairperson), Harvard School of Public Health, Department of Immunology and Infectious Diseases, 665 Huntington Avenue, Boston, MA 02115-6021, USA. Tel.: +1 (617) 432 1563 Fax: +1 (617) 432 4766 or 738 4914 E-mail: [email protected]

Dr Eve Worrall, London School of Hygiene and Tropical Medicine, Health Policy Unit, Keppel Street, London WC1E 7HT, United Kingdom. Tel.: +44 207 927 2354 Fax: +44 207 637 5391 E-mail: [email protected]

*Professor Yongyuth Yuthavong, Senior Researcher, Biotec, National Science & Technology Development Agency, 73/1, Rama VI Road, Rajdhevee, Bangkok 10400, Thailand. Tel.: +662 644 8002 Fax: +662 644 8022 E-mail: [email protected]

Dr Mark W. Young, Roll Back Malaria, Health Section, Programme Division, UNICEF, Three United Nations Plaza, New York, NY 10017, USA. Tel.: +1 212 303 7966 Fax: +1 212 824 6460 E-mail: [email protected]

Representatives of partner institutions


The Global Fund to Fight AIDS, Tuberculosis and Malaria

*Dr Vinand Nantulya, Director for Strategy & Evaluation, Avenue Louis Casai 53, Cointrin CH-1216, Geneva, Switzerland. Tel.: +41 22 791 1700 Fax: +41 22 791 1701 E-mail: [email protected]

National Institutes of Health

*Dr Michael Gottlieb, Parasitology and International Programs Branch, National Institute of Allergy and Infectious Diseases, Department of Health and Human Services, 6610 Rockledge Drive/Room 5099, Bethesda, MD 20892-6603, USA. Tel.: +1 (301) 435 2861 Fax: +1 (301) 402 0659 E-mail: [email protected]

Dr Barbara J. Sina, National Institutes of Health, Fogarty International Centre, Building 31 Room BZC39, Bethesda, MD 20892, USA. Tel.: +1 (301) 402 9467 Fax: +1 (301) 402 0779 E-mail: [email protected]

GlaxoSmithKline

Mr Ian C. Boulton, Director, Commercial Strategy, Diseases of the Developing World, Global Commercial Strategy, GlaxoSmithKline House, Brentford, United Kingdom. Tel.: +44 20 8047 4711 Fax: +44 20 8047 6919/8800 4711 E-mail: [email protected]


AFRO

*Dr Thomas Sukwa, Research and Product Development for Communicable Diseases, Parirenyatwa Hospital, PO Box BE 773, Harare, Zimbabwe. Tel.: +1 321 733 9244 Fax: +1 321 733 9020 E-mail: mailto:[email protected]

AMRO

*Dr Zaida Yadon, HCT/PAHO, Research and Product Development for Communicable Diseases, Pan American Sanitary Bureau, 525, 23rd Street, NW, Washington, DC 20037, USA. Tel.: +1 202 974 3000 Fax: +1 202 974 3663 E-mail: [email protected]

EMRO

*Dr Hoda Atta, MAL, WHO Post Office, Abdul Razzak Al Sanhouri Street, Naser City, Cairo, Egypt. Tel.: +202 670 2535 E-mail: [email protected]

*Dr Z. S. Hallaj, CDC, WHO Post office, Abdul Razzak Al Sanhouri Street, Naser City, Cairo, Egypt. Tel.: +202 760 2535 Fax: +202 670 2492 E-mail: [email protected]

EURO

Dr Mikhail Ejov, MAL, 8, Scherfigsvej, DK-2100 Copenhagen, Denmark. Tel.: +45 39 171 717 Fax: +45 39 171 818 E-mail: [email protected]

SEARO

*Dr Chusak Prasittisuk, Research and Product Development for Communicable Diseases, New Delhi 110 002, India. Tel.: +91 11 337 0804 ext.: 26115 Fax: +91 11 337 9507/337 8412 E-mail: [email protected]

WPRO

*Dr David Bell, Global Focal Point on Malaria Rapid Diagnostics, PO Box 2932, Manila 1099, Philippines.

Tel.: +632 528 9756 E-mail: [email protected]

*Dr Kevin Palmer, Communicable Disease Prevention Eradication and Control. PO Box 2932, Manila 1099, Philippines.

Tel.: +632 528 8001 Fax: +632 5211 036 E-mail: [email protected]

WHO Regional Advisers

WHO/HQ Secretariat


Dr David Alnwick, Director, Roll Back Malaria (RBM)

Dr James J. Banda, Communicable Diseases (CDS)/RBM partnership

Dr Mary Bendig, TDR/ Product Research & Development (PRD)

Mr Erik Blas, Programme Manager, UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR)

*Dr Robert Bos, Protection of the Human Environment (PHE)/ Water, Sanitation and Health (WSH)

Dr Kabir Cham, CDS/ Malaria Control (MAL)

Dr Jane Crawley, CDS/MAL

Dr Charles Delacollette, CDS/MAL

Dr Hashim Ghalib, TDR/ Research Capability Strengthening (RCS)

Dr Melba Gomes, TDR/ Intervention Development and Implementation Research (IDE)

Dr Pierre Guillet, CDS/ Control, Prevention & Eradication (CPE)

Dr Traore Fatoumata Nafo, Executive Secretary CDS/RBM Partnership

Dr David Heymann, Executive Director, CDS

Dr Thomas Kanyok, TDR/PRD

Dr Juntra Karbwang, TDR/PRD

Dr Lindiwe Makubalo, TDR/IDE

Dr Kamini Mendis, CDS/MAL

Dr Carlos Morel, Director TDR


Dr Bernard Nahlen, CDS/MAL

*Dr Mike Nathan, CDS/CPE

Ms A. Odugleh, CDS/CPE

Dr Ayoade Oduola, TDR/ Basic & Strategic Research (STR)

Dr Olumide Ogundahunsi, TDR/RCS

Dr Piero Olliaro, TDR/PRD

Dr Franco Pagnoni, TDR/ IDE

*Dr Will Parks, CDS/CPE

Dr Mark Perkins, TDR/PRD

Dr J.H.F. Remme, TDR/IDE

*Dr Elil Renganathan, CDS/CPE

Dr Robert Ridley, TDR/PRD

Dr Pascal Ringwald, CDS/Communicable Disease Surveillance & Response (CSR)

Dr Allan Schapira, CDS/MAL

Dr Johannes Sommerfeld, TDR/STR

Dr Awash Teklehaimanot, CDS/RBM partnership

Dr Thomas Teuscher, CDS/RBM partnership

Mr Steven Wayling, TDR/RCS

Dr Morteza Zaim, CDS/CPE

Dr Fabio Zicker, TDR/RCS

TDR Disease Research Coordinators

Dr Lester Chitsulo: schistosomiasis

Dr Philippe Desjeux: leishmaniasis

Dr Howard Engers: dengue/leprosy

Dr Deborah Kioy: African trypanosomiasis

Dr Janis Lazdins: focal point for disease research coor-dinators

Dr Philip Chukwuka Onyebujoh: tuberculosis

Dr Yeya T. Touré: malaria


Mal

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Annex 3 WORKING PAPER: Effective management of childhood malaria at the community level: programme experience to guide the research agenda


EFFECTIVE MANAGEMENT OF CHILDHOOD MALARIA AT THE COMMUNITY LEVEL: PROGRAMME EXPERIENCE TO GUIDE THE RESEARCH AGENDA

Mark W. YoungSenior Advisor, Roll Back MalariaUNICEF, New York, USA

1. INTRODUCTION

Approximately 1 million young children in Africa die from malaria every year. Partly as a result of the burden of malaria, mortality rates for children aged less than 5 years have generally remained stag-nant over the past decade in Africa. The Millennium Development Goals and goals contained in the out-come document of the recent United Nations Special Session on Children, A world fit for children1, provide a focus for scaling-up programmes for improving child survival: – To “reduce by one-third, by 2010, the infant and

under-five mortality rate, in pursuit of the goal of reducing it by two-thirds by 2015”;

– To “reduce by one half the burden of disease associated with malaria by 2010”; and

– To “have halted by 2015 and begun to reverse the incidence of malaria and other major diseases”.

Effective management of childhood malaria must therefore be a key element in the approach of the Roll Back Malaria programme to achieve these goals. The key coverage target included in the Abuja Malaria Declaration2 and A world fit for children serves as a guide for programmes aimed at the effective man-agement of malaria in children: of children aged less than 5 years, 60% should have access to appropriate treatment for malaria within 24 hours of the onset of symptoms.

Most children die from malaria at home without receiving adequate therapy. Only a small number of children with fever are treated at health-care facili-ties, with Demographic Health Survey (DHS) data from 14 countries in Africa suggesting that between 16% and 71% of children aged less than 5 years with fever are treated in a health-care facility. This obvi-

ates the need for bringing malaria case management as close to the home as possible.

Other papers in this report deal with the manage-ment of severe illness, combination therapy, and other issues that are obviously relevant to the man-agement of malaria in children. Therefore, this paper will not address these issues in detail but will deal specifically with “out-of-facility management of non-life-threatening febrile illness in malaria-endemic Africa”.

A number of elements are critical to management of the child with fever:– The caregiver must recognize the illness as

potential malaria and provide the appropri-ate dose of an antimalarial drug, together with supportive care. This requires attention to care practices, communication, and drug dosing characteristics.

– An efficacious antimalarial drug must be avail-able either in the home or near the home when the child becomes ill. This requires attention to national policy formulation, monitoring of drug resistance, and drug procurement and distribu-tion.

– The drug must be affordable for the caregiv-er. This requires attention to drug pricing and financing.

– The caregiver must recognize when the illness is severe or not improving and have the means to take the child to health-care facilities. Again, care-seeking is an important issue here, along with community capacity development and referral systems.

On the basis of these elements and drawing on exten-sive experience of control programmes from differ-ent countries, this paper examines critical issues and challenges, and identifies key research priorities for the effective management of childhood malaria. The critical issues that emerge in the approach to the child with malaria are:– Recognizing when therapy for malaria is indi-

cated;– Making available the most efficacious drug as

close to the child as possible;– Managing the child with chronic infection with

malaria and anaemia;– “Prevention is the best medicine”.

1 United Nations Special Session on Children, 8–10 May 2002, http://www.unicef.org/specialsession/wffc/index.html2 The Abuja Malaria Declaration, http://mosquito.who.int/docs/abuja_declaration.pdf.


2. RECOGNIZING WHEN THERAPY FOR MALARIA IS INDICATED

Multiple disease processes often coexist in a sick child. In areas in which malaria is endemic, the child with fever may be suffering from malaria, pneumo-nia, diarrhoea, measles, or a combination of these, in addition to malnutrition. At health-care facilities, the management of the sick child at is generally based on symptoms, for example the Integrated Management of Childhood Illness (IMCI) algorithms, which rec-ommend that in high-transmission, malaria-endemic areas, all children aged less than 5 years (“under-fives”) with fever be treated with antimalarials. In the absence of diagnostic laboratory facilities, some con-ditions are often indistinguishable, even for skilled health-care workers. As differentiation is often dif-ficult for trained clinicians, it is unlikely that a high specificity for the diagnosis of malaria in the commu-nity setting can be achieved by community health-care workers, shopkeepers, or caregivers.

Pneumonia, for example, is also a major cause of death of children in sub-Saharan Africa, and is esti-mated to be the cause of about 20% of mortality in childhood. According to IMCI, “malaria” is defined as presence or history of fever, symptoms that also occur in children with pneumonia. “Pneumonia” is defined as cough or difficult breathing, with rapid breathing or chest indrawing, symptoms also indicating severe malaria. The symptom over-lap between malaria and pneumonia is high, and recent studies indicate that in areas in which malar-ia is endemic many children who fulfil the case def-inition for malaria also fulfil the case definition for pneumonia. These children therefore require treat-ment with both an antimalarial and an antibiotic.

With programmes for the home management of malaria bringing malaria-specific education and treatment of fever to the community level, this has implications for the management of the sick child. Treating a child with fever with only an antimalarial will leave many cases of pneumonia untreated. This may result in delayed care-seeking for pneumonia and other underlying conditions, when caregivers feel that their child has been adequately treated for the current illness. The result will be continued high rates of death in childhood. There is a need to con-vince policy-makers and practitioners that drugs for managing pneumonia can also be safely adminis-tered in a community setting, and that lives can be saved as a result.

Considering this reality, any attempt in the current context of diagnostic capabilities in rural Africa to improve clinical diagnosis of malaria-specific illness

will be difficult. Much work has gone into the study of clinical algorithms for fever, and this is what the present IMCI algorithms have attempted to address. Priority at this time should be given to developing an approach to the management of the sick child, with a focus on defining those therapies from which the child would most benefit, and assure that the “essential” efficacious drugs to manage the majori-ty of potentially serious/fatal disease processes are available.

In areas where the prevalence of malaria parasitae-mia is high, the co-administration of an antimalar-ial drug to a child with a febrile illness should be viewed as good medical care. This is valid even if parasitaemia is not the primary cause of the fever (which cannot be defined accurately in the commu-nity), because parasitemia can impair the capacity of the child to recover from the primary infection (e.g. pneumonia) or chronic sequelae (e.g. anaemia). The reality is that judicious “polytherapy” will produce the greatest reduction in morbidity and mortality from childhood febrile illness.

2.1 Prompt recognition of illness and danger signs by caregivers

Caregivers must recognize the signs and symp-toms of illness (including danger signs) and pro-vide appropriate treatment and care. An effective communication programme to improve care prac-tices is therefore an essential component of any pro-gramme to support appropriate home management of malaria. It is evident that change in behaviour at the individual level is still lagging far behind expec-tations, in spite of a high degree of awareness gener-ated by carefully delivered public health messages. New communication methods and strategies need to be found to respond to this reality, on the basis of the premise that sustainable change in behaviour and practices is heavily influenced by societal pres-sures and support systems that operate in families and communities.

Community capacity development through commu-nity dialogue has the greatest potential for induc-ing sustained change in behaviour and improving care practices, including care-seeking and treatment for malaria. Communities that have been mobi-lized through community dialogue and other par-ticipatory communication approaches demonstrate increased awareness and improved health practices.

Priorities for research include:

• Investigation of drug therapy options for the co-management of malaria, pneumonia and other concurrent illness in the sick child;


• Operational research programme for the effec-tive joint treatment of malaria and pneumonia/acute respiratory infections (ARI) at the commu-nity level; and

• Effective communication strategies to improve care practices at the community level.

3. MAKING AVAILABLE THE MOST EFFECTIVE DRUG AS CLOSE TO THE CHILD AS POSSIBLE

There is often only “one shot” at getting adequate antimalarial therapy for a child; national pro-grammes need to make the most of this one oppor-tunity. At an individual level, it is known that prompt treatment with an efficacious antimalar-ial clears malaria parasitaemia and reduces anae-mia. Therefore programmes must use treatment that will be most effective in reaching children as close to home as possible in an operational setting at the community level. Antimalarial treatment aims to save children’s lives, and saving lives requires an effective programme in the “real-life situation”.

The effectiveness of a programme for the treatment of malaria is determined by multiple factors, in addi-tion to drug efficacy. The characteristics of “close-to-home” therapy that will ensure programme effectiveness include:– Use of drugs that are efficacious, safe, and

affordable;– Treatment that is available in or near the home;– The number and frequency of doses – “first-

dose efficacy”;– Functioning referral systems, and community-

level treatment for the ill child who is unable to take oral antimalarials.

3.1 Drugs that are efficacious, safe, and affordable

Currently, the debate around the formulation of pol-icy regarding therapy with antimalarial drugs has several elements, which need to be addressed to assure optimal therapy.

First, it is necessary to have accurate monitoring of the efficacy of the drug against P. falciparum in subregions of Africa. For more than two decades, the resistance of Plasmodium falciparum to common-ly-used antimalarial drugs has been an evolving public health challenge in the control of malaria in Africa. Resistance to chloroquine is present through-out most of Africa, with the exception of some sub-Sahel zones in west Africa. Furthermore, resistance to drugs that have been introduced to replace chlo-roquine (e.g. sulfadoxine/pyrimethamine or SP) is

developing. During the past 5 years, there has been great attention to monitoring of the spread and intensification of drug resistance. Several nations in east Africa have responded to data demonstrat-ing that chloroquine is no longer efficacious by changing their leading drug for antimalarial thera-py to sulfadoxine/pyrimethamine (Fansidar). This change was made in 1993 in Malawi, where a sig-nificant decrease in child mortality, with no measur-able increase in drug-associated adverse effects, has since been demonstrated.

Second, national regulatory authorities require information on the safety of candidate antimalari-al drugs, to assess whether particular drugs can be incorporated into a national programme. Of note is the fact that co-formulated drugs containing arte-misinin are not currently approved for use in young children, one of the populations that are most at risk. With regard to safety and efficacy, that there is an extensive problem with counterfeit and substan-dard pharmaceuticals in Africa. It has been estimat-ed that in several countries most seriously affected by drug resistance, as many as one-third of antima-larials may be counterfeit or substandard.

Third, in the future, antimalarial drugs will cost more than chloroquine and SP, and the internation-al community must address the financing of anti-malarial drug procurement with this perspective. The Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM) could play a pivotal role in mak-ing available substantially more effective therapy where lives can be saved.

Research priorities:

• Investigation of patterns of drug sensitivity of P. falciparum, and accurate monitoring of drug effi-cacy.

• Quality and safety of candidate antimalari-al drugs. In particular, the safety of new arte-misinin-containing co-formulations for use in young children, and systems for monitoring quality control and adverse drug reactions, must be assured.

• Cost and financing issues should be addressed in collaboration with national governments, the World Bank, donors, and the wider international community.

3.2 Treatment that is available in or near the home: home-based management of fever

Many episodes of malaria are currently treated out-side the formal health system, often with inappro-priate or incorrectly used drugs. This is particularly common in more rural and remote populations and


contributes both to worsening morbidity patterns and increased drug resistance. Programmes for the home management of malaria aim to improve early home-based treatment practices through improved access to, and information on, effective antimalarial drugs. Although experience with large-scale home management programmes is limited, there is evi-dence currently available to support this approach:– Use of pre-packaged antimalarials has signifi-

cantly increased the number of children receiv-ing treatment within 24 hours in studies in Uganda and Nigeria, and significantly reduced progression to severe disease in Burkina Faso.

– A community-based programme in Ghana, which used trained volunteers to provide infor-mation, pre-packaged drugs, and follow-up of children with fever, led to effective use, improved compliance, and improved care.

– Significant reduction in mortality in children aged less than 5 years was achieved in Ethiopia through training of local coordinators to teach mothers to recognize the symptoms of malaria and to give antimalarial treatment promptly.

– In Kenya, training of shopkeepers in the appro-priate choice and dose of antimalarial drugs for the treatment of childhood fever can lead to more effective management.

Uganda has recently started going to scale with a national programme for home-based management of fever, using pre-packaged drugs, initially start-ed in 10 districts. Reports from Uganda indicate that, despite challenges, there is good community involvement and mothers are able to manage malar-ia effectively. District-level data indicate that the programme is effective, and results in the lowering of morbidity and mortality among children.

Programmes must look for “windows of opportu-nity” for delivering effective antimalarials. Having appropriate messages and pre-packaged efficacious antimalarials at various “contact points” between the health system and children (or their caregivers) is likely to result in increased coverage of prompt treatment for malaria. These could include:– Routine visits (static and outreach) for

immunizations (Expanded Programme on Immunization, EPI);

– Other routine health visits, e.g. growth monitor-ing (static or outreach);

– Child Health Days or other campaigns (such as that for measles);

– Food distribution points, and nutritional reha-bilitation programmes;

– Local shopkeepers;


• Cost and effectiveness of large-scale pro-grammes for the home management of malaria;

• Programmatic issues such as training/capaci-ty building, drug procurement and supply, and monitoring and evaluation;

• Appropriate packaging and information that should accompany the treatment;

• Effectiveness of the delivery of pre-packaged antimalarials through various “contact points” in the system.

3.3 The number and frequency of doses: “first-dose efficacy”

Adherence to multiple dose/multiple day drug reg-imens is suboptimal when compared with simpler regimens, such as one-dose therapy. The “first-dose efficacy” of an antimalarial is therefore critical to programme effectiveness. For example, the effective-ness of SP given as part of a programme is equiva-lent to that of SP given by directly observed therapy. Experience suggests that antimalarials given over longer periods (e.g. 5–7 days) are unlikely to result in complete treatment, particularly as the child feels better or if any adverse effects are present.


• First-dose efficacy of drugs;• Identification of antimalarials with short-course

dosing regimens, and investigation on how to im–prove compliance with regimens lasting 2–3 days.

3.4 Functioning referral systems, and community-level treatment for the ill child who is unable to take oral antimalarials

There are limitations to referral in most rural set-tings, generally related to health system issues such as delayed or unavailable transport. However, efforts to strengthen health systems take time, and effective treatment for complicated/severe malaria should be available close to the community for those children who cannot be quickly referred. Artesunate suppositories, given either at home or at an entry-level health-care facility, are a potentially useful way of providing effective emergency treatment for chil-dren who are unable to take oral medication.


• How to best treat the child at the periphery who is unable to take oral antimalarials. What is the role of artesunate suppositories – when, where and how to use?

• Mechanisms to ensure that the child is followed up, and that the present episode has been fully treated.


4. MANAGEMENT OF “CHRONIC DISEASE” AND ANAEMIA

Effective treatment for childhood malaria is as much about the management of “chronic disease” as it is about the management of acute febrile ill-ness. Anaemia is a frequent consequence of malar-ia in many parts of the world, and chronic anaemia adversely affects physical and cognitive develop-ment. Repeated episodes of malaria, and inadequate-ly treated illness, can lead to severe, life-threatening anaemia. Blood transfusions, which may be life-sav-ing in these circumstances, can expose the child to the risk of infection with human immunodeficiency virus (HIV) and other blood-borne agents.

The management of anaemia with the concurrent administration of antimalarials and micronutrient supplements has demonstrated marked improve-ment in the haematological status of young children. In addition, the management of malaria at the house-hold level goes beyond simply “drug therapy”. The child with chronic malaria and anaemia often also suffers from overall poor nutritional status. Good feeding practices – increased fluids, increased food intake and continued feeding – lead to better health outcomes in the sick child. Front-line health work-ers and other managers at the community level can reinforce these practices.


• The implications of large-scale programmes in which iron supplements and antimalarial drugs are administered concurrently, including the role of additional micronutrients, such as vitamin A and zinc.

• Strategies to improve the nutritional status of the sick child.

5. “PREVENTION IS THE BEST MEDICINE”

Use of effective prevention measures reduces mor-bidity and the transmission of malaria:– Use of insecticide-treated nets (ITN) reduces

fever, illness and anaemia caused by malaria;– High coverage with ITNs at the household level

reduces vector transmission; – Intermittent preventive treatment (IPT) for

infants reduces morbidity and anaemia caused by malaria.

Better prevention means less illness caused by malar-ia, and therefore fewer children requiring treatment. Prevention must be emphasized as part of an inte-grated malaria control programme. Ensuring that ITNs are used among the highest possible propor-

tion of young children is a priority, and therefore financing and distribution of ITNs within large-scale national programmes targeted at young chil-dren must be assured.


• Defining the most effective and efficient approaches to the delivery of ITNs for use by young children;

• Further research on infant IPT linked to rou-tine EPI programmes, including large-scale pro-gramme delivery (impact on EPI coverage; cost–effectiveness; infant formulations of drugs; impact on anaemia and mortality in a pro-gramme setting).

6. CONCLUSIONS

The way forward is to support research that pro-vides national programmes with information that addresses the broad range of capacities required to assure that effective antimalarial therapy is avail-able nearby when children become sick. To accom-plish this objective, national policy-makers and programme-managers will benefit from research support in the areas identified above.

While new and more efficacious drugs and drug combinations will hopefully become affordable and available in Africa in the not-too-distant future, improved services for child survival cannot wait for that day. There must be a coordinated commit-ment to optimizing the use of drugs that are cur-rently available, and to support the development of effective drug procurement and delivery logis-tics that will be sustained, irrespective of the drugs being recommended.

A criticism of this approach could be that deploy-ment of drugs for use by caregivers at the house-hold level might intensify the development of drug resistance. At the present time, much of the treat-ment provided at the household level uses ineffec-tive drugs in inappropriate doses. Under-dosing is associated with poorer clinical outcomes, often manifested in children as anaemia. Providing effi-cacious drugs through a programme approach in a format that is likely to result in complete treatment, should result in the development of fewer resistant parasites. This tension between “saving lives” and “saving drugs” can be further alleviated by the wide deployment and use of preventive measures in order to reduce the transmission of the malaria parasite.


References on which this text is based

Breman JG & Campbell CC (1988). Combating severe malaria in African children. Bulletin of the World Health Organization,65:611–620.

Greenwood BM et al. (1987). Mortality and morbidi-ty from malaria among children in a rural area of The Gambia, West Africa. Transactions of the Royal Society of Tropical Medicine and Hygiene, 81:478–486.

Kidane G & Morrow RH (2000). Teaching moth-ers to provide home treatment of malaria in Tigray, Ethiopia: a randomised trial. The Lancet, 356:550–555

Menendez C et al. (1997). Randomised placebo-con-trolled trial of iron supplementation and malaria che-moprophylaxis for prevention of severe anaemia and malaria in Tanzanian infants. The Lancet, 350:844–850.

Nicoll A (2000). Integrated management of childhood illness in resource-poor countries: an initiative from the World Health Organization. Transactions of the Royal Society of Tropical Medicine and Hygiene, 94:9–11.

O’Dempsey TJ et al. (1993). Overlap in the clinical fea-tures of pneumonia and malaria in African children. Transactions of the Royal Society of Tropical Medicine and Hygiene, 87:662–665.

Schellenberg D et al. (2001). Intermittent treatment for malaria and anaemia control at time of routine vacci-nations in Tanzanian infants: a randomised, placebo-controlled trial. The Lancet, 357:1471–1477.

Sirima SB et al. (2003). Self-treatment with pre-pack-aged antimalarials in Burkina Faso. Tropical Medicine & International Health, 8:133–139

Slutsker L et al. (1994). Treatment of malaria fever epi-sodes among children in Malawi: results of a KAP survey. Tropical Medicine and Parasitology, 45:61–64

WHO (2001). Antimalarial drug combination therapy : report of a WHO technical consultation, 4–5 April 2001 Global Partnership to Roll Back Malaria. Geneva, World Health Organization (WHO/CDS/RBM/2001.35; http://whqlibdoc.who.int/hq/2001/WHO_CDS_RBM_2001.35.pdf, accessed 28 April 2004).

WHO (2002). Addressing the challenge of financing antimalarial treatments in Africa: proposals for glo-bal action. In: Improving access to antimalarial medicines: report of the RBM partnership meeting, 30 September–2 October 2002. Global Partnership to Roll Back Malaria. Geneva, World Health Organization (WHO/CDS/RBM/2003.44; http://whqlibdoc.who.int/hq/2003/WHO_CDS_RBM_2003.44.pdf, accessed 28 April 2004).


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Annex 4 WORKING PAPER: Prevention of malaria in pregnancy


PREVENTION OF MALARIA IN PREGNANCY

Feiko ter Kuile and Robert NewmanMalaria Epidemiology BranchCenters for Disease Control and PreventionDivision of Parasitic DiseasesAtlanta, Georgia, USA

1. INTRODUCTION

Pregnant women are more susceptible to malar-ia than non-pregnant women. The adverse conse-quences vary depending on the pre-existing level of immunity against malaria and range from severe malaria resulting in maternal and fetal death, in areas of epidemic and unstable transmission of malaria, to predominantly low-grade, sometimes sub-pat-ent parasitaemia, in areas of stable transmission. Infections of the latter type frequently do not result in acute symptoms, and remain therefore undetected and untreated. They are, however, a substantial cause of maternal anaemia, and may be responsible for 30–35% of preventable low birth weight (Steketee et al. 2001). Women giving birth for the first or second time (primi– and secundi gravidae) are most at risk, but in areas with a high prevalence of infection with HIV, women of higher gravidity are also affected.

A series of studies recently reported that P. fal-ciparum binds selectively to chondroitin sulfate A (CSA) expressed in the placenta (Fried & Duffy, 1996). Unlike primigravidae, women who have had placental malaria in previous pregnancies pos-sess anti-adhesion antibodies that inhibit placental sequestration of this distinct subpopulation of para-sites with the CSA-binding phenotype (Fried et al., 1998). If this is the main mechanism of the parity-specific adverse effects of malaria in pregnancy, then vaccination against these specific parasites may one day be possible (Greenwood, 2001).

Until then, the control of malaria in pregnancy relies on a three-pronged approach (WHO, 2000a): – Use of intermittent preventive treatment (IPT),

provided as part of antenatal care; – Insecticide-treated nets (ITNs); and – Malaria case management.

In this paper we will discuss the available scientific evidence concerning IPT with sulphadoxine/pyri-methamine (SP), remaining gaps in our knowledge, and potential alternative antimalarials. We also dis-cuss the recent research findings regarding use of ITNs in pregnancy.

2. INTERMITTENT PREVENTIVE TREATMENT WITH SULPHADOXINE/PYRIMETHAMINE

Presently only one antimalarial, sulphadoxine/pyri-methamine (SP), is used for intermittent preventive treatment (IPT), although research with chloroquine is in progress. SP is effective, safe and has good pro-gramme feasibility (it is well-accepted and can be given as a single dose by directly-observed therapy). The current scientific evidence on IPT-SP was sum-marized at a recent meeting to develop a strategic framework for malaria control during pregnancy in the WHO Africa Region (Table 1) (WHO, 2002).

2.1 Gaps in knowledge

Coverage

Evaluation of the coverage of IPT-SP in Kenya and Malawi showed that although a high proportion (70–95%) of women attending antenatal care clin-ics received the first dose, only 10–40% received the second dose (Rogerson et al., 2000; Ashwood-Smith et al., 2002; Eijk et al., 2004). Thus, despite the high potential programme feasibility (Newman et al., 2003), the uptake of IPT-SP has been slow in these countries. Delivery of IPT with each sched-uled monthly visit, instead of once per trimester may increase the proportion of women receiving at least two doses. Operations research into ways to

1 At least two IPT doses are required to achieve optimal benefit in most women

2 In women infected with HIV, one study has demonstrated that monthly dosing of IPT (with most women getting three to four doses) was necessary to achieve optimal benefit

3 To achieve optimal benefit in settings in which the prevalence of HIV in pregnant women is greater than 12%, it is more cost-effective to treat all women with a three-dose regimen than to screen for HIV and provide this regimen only to HIV-positive women

4 There is no evidence of any additional risk associated with receiving a third dose of IPT

5 There is no evidence to suggest that receiving more than three doses of IPT during pregnancy offers additional benefit

Table 1. Current scientific evidence on dosing regimens for intermittent preventive therapy with SP

From WHO (2002)


increase coverage and early use of the services of antenatal care clinics is required.

Folate supplementation and antifolate antima-larials

Supplementation with folic acid is known to reduce the antimalarial efficacy of the antifolate SP (van Hensbroek et al., 1995). However, supplementation with haematinics, including folate, is part of routine antenatal care in many countries that use IPT-SP. No studies have been completed that address the poten-tial interaction between SP and folic acid in preg-nant women, but several trials are planned.

IPT-SP in HIV-positive women receiving cot-rimoxazole as prophylaxis for infection with Pneumocystis carinii

As HIV seroprevalence rises across Africa, an increasing number of women will receive prophy-lactic treatment with cotrimoxazole for infection with Pneumocystis carinii. Because cotrimoxazole and SP are both drugs that contain sulfur (“sulfa” drugs), it is inadvisable to administer IPT-SP to a woman who is already receiving cotrimoxazole for Pneumocystis carinii prophylaxis. There is need to determine whether these women are adequately protected from malaria by cotrimoxazole, or wheth-er they should receive a safe non-sulfa alternative for IPT.

Optimal dosing regimen

Infection with HIV reduces the efficacy of intermit-tent preventive treatment (Parise et al., 1998). New WHO guidelines recommend a schedule of four vis-its to an antenatal care clinic, with three visits after quickening. The giving of IPT with each scheduled visit is likely to ensure that a high proportion of women receive at least two doses. It is not known whether HIV-positive women benefit from addi-tional (i.e. monthly) doses of SP. A study comparing two doses versus monthly IPT-SP in HIV-positive and HIV-negative women is underway in Malawi.

IPT as a function of transmission intensity and seasonality

The benefits of perennial versus seasonal implemen-tation of IPT in areas with highly seasonal transmis-sion of malaria require further study. Further, more information is required on the efficacy of IPT in areas with low transmission of malaria. It is unclear at what level of transmission IPT would no longer be cost-effective, and febrile case management or other methods of prevention (e.g. ITNs) would be favoured. Similar considerations may apply to set-tings with markedly reduced intensity of transmis-

sion due to area-wide reductions in the densities of malaria-transmitting mosquitoes after widespread deployment of ITNs. Epidemics of malaria pose a particular problem and are associated with poten-tially high maternal and fetal morbidity and mortali-ty. More research is required to compare intervention strategies in these settings (e.g. monthly IPT and ITNs).

Safety of SP

Adverse skin reactions are minimal with the two- or three-dose regimen for IPT-SP, including in women infected with HIV. Continued monitoring is required, particularly when more frequent (month-ly) administration of IPT-SP is considered for HIV-infected individuals, and with the potential for frequent (self-)treatment with other sulfa containing drugs (e.g. cotrimoxazole) in this risk group.

Use of SP in the last 4 weeks of pregnancy has his-torically been discouraged because of the theoret-ical risk of kernicturus in the newborn. Results of studies to date that have followed infants during the neonatal period indicate this is not a problem with IPT-SP, and new WHO guidelines for preven-tion of malaria in sub-Saharan Africa no longer rec-ommend this restriction (WHO, 2002).

3. ALTERNATIVE ANTIMALARIALS

Newman and colleagues recently evaluated poten-tial alternative antimalarials for use as IPT in preg-nancy (Newman et al., 2003). They used two central considerations; safety for the mother and fetus; and effectiveness, as determined by efficacy, cost, avail-ability, deliverability, and acceptability of the drug. Potential drugs or drug combinations were ranked in order of predicted effectiveness for use in preven-tion programmes (Table 2 and 3).

Currently, IPT-SP is predicted to have the best over-all effectiveness (Table 2). Its low cost, wide avail-ability, easy deliverability, and acceptability make it the clear choice in countries where efficacy of the drug remains good. The following combinations of drugs are attractive alternatives to monothera-py with SP that require urgent evaluation for use in pregnancy: – amodiaquine (alone and in combination with SP

or artesunate);– chlorproguanil-dapsone (LapDap with and

without artesunate);– artesunate plus SP; and – artemether-lumefantrine.


3.1 Amodiaquine, and amodiaquine plus SP

Cameroon has recently changed its policy regard-ing the prevention of malaria during pregnancy, abandoning chemoprophylaxis with chloroquine in favour of IPT with amodiaquine (Leke R, person-al communication). There are no published data regarding the efficacy of amodiaquine for IPT and only minimal data regarding its safety for treatment of malaria during pregnancy (Steketee et al. 1987; McDermott et al., 1988; Naing et al., 1988; Thet et al., 1988. Amodiaquine is slightly more expensive than chloroquine (US$ 0.30 for a 2-course IPT regimen) and its availability is patchy, as it has been taken

off the formulary of some countries because of con-cerns over its safety. Its acceptability is fairly good; it is not as bitter a drug as chloroquine, but some patients experience dizziness.

The combination of amodiaquine and SP is an attrac-tive alternative (McIntosh, 2001), which has not been evaluated in pregnancy. A series of recent studies in areas of east Africa where chloroquine-resistant malaria is found demonstrated consistently better efficacy with amodiaquine plus SP than with amo-diaquine or SP alone in children (Dorsey et al., 2001; Gasasira et al., 2001; Kamya et al., 2001; Staedke et al., 2001). The cost of this combination (US$ 0.46 for

Table 2. Comparison of effectiveness of antimalarial drug regimens used for the prevention of malaria in pregnant women From Newman et al. (2003)

Drug Regimena Cost(1–5)

Localavailability

(1–3)

Deliverability(1–5)

Acceptability (1–3)

Total scoreb

(Ideal efficacy=1)Total scoreb

(Poor efficacy=4)

Sulfadoxine/pyrimethamine IPT 1 1 1 1 5 8

Chloroquine IPT 1 1 2 3 8 11

Amodiaquine IPT 2 2 2 2 9 12

Amodiaquine + SP IPT 2 2 2 2 9 12

Chlorproguanil-dapsone (Lapdap)c IPT 2 3 2 1 9 12

Sulfadoxine/pyrimethamine + artesunate

IPT 4 2 2 1 10 13

Artemether-lumefantrine (Riamet; Coartem)

IPT 4 2 2 1 10 13

Pyrimethamine-dapsone (Maloprim) Cpx 3 2 3 1 10 13

Amodiaquine + artesunate IPT 4 2 2 2 11 14

Chlorproguanil-dapsone + artesunate

IPT 4 3 2 1 11 14

Chloroquine Cpx 2 1 4 3 11 14

Atovaquone-proguanil (Malarone) IPT 5 3 2 1 12 15

Mefloquine IPT 4 3 2 3 13 16

Mefloquine + artesunate IPT 5 3 2 3 14 17

Atovaquone-proguanil (Malarone) Cpx 5 3 5 1 15 18

Azithromycin Cpx 5 3 5 1 15 18

Proguanil + chloroquine Cpx 4 2 5 3 15 18

Mefloquine Cpx 5 3 4 3 16 19

a Regimen: IPT, intermittent preventive treatment; Cpx, chemoprophylaxis.b A low overall score is indicative of “good” overall effectiveness for the regimen.Scoring system is as follows: Efficacy: 1 = > 95% ACPR; 2 = 85–94% ACPR; 3 = 75–84% ACPR; 4 = 60–74% ACPR; 5 = < 60% ACPR, where APCR = adequate clinical and parasitilogical responseCost: 1 = US$ 0.01– US$ 0.25; 2 = US$ 0.26–0.50; 3 = US$ 0.51–$1.50; 4 = US$ 1.51–$5.00; 5 = > US$ 5.00.Local availability: 1 = on national formulary, widely available; 2 = on national formulary, not widely available; 3 = not on national formulary. Deliverability: 1 = two- or three-course IPT with a single treatment dose that can be given under observation; 2 = two- or three-course IPT with multiple treatment doses, some of which must be taken unsupervised; 3 = monthly or biweekly dosing for IPT/chemoprophylaxis; 4 = weekly chemoprophylaxis; 5 = daily chemoprophylaxis.Acceptability: 1 = generally acceptable; 1 point can then be added for each of the following categories, bitter taste/pregnancy-related taboos, other adverse reactions (such as itching or dizziness), up to a maximum of 3 points.Scores are best used for comparative purposes between drugs and regimens. Note that drugs with a score of 5 for efficacy (< 60% adequate clinical and parasitilogical response [ACPR]) should not be given an overall score, and should be excluded from consideration for use in programmes. Worst-case efficacy for scoring purposes is therefore efficacy = 4 (60–74% ACPR).

c Lapdap is currently in commercial development; its components (chlorproguanil and dapsone) are available.


two-dose IPT) is moderate, and its combined effec-tiveness score was predicted to be good (Table 2).

3.2 Chlorproguanil-dapsone (Lapdap)

The results of studies in children have demonstrated that the safety of chlorproguanil-dapsone (Lapdap) is good (Mutabingwa et al., 2001; Winstanley, 2001; Sulo et al., 2002), although one trial did find a higher rate of severe anaemia among children treated with Lapdap than among those treated with SP (Sulo et al., 2002). Given that the component drugs are both considered safe for use in pregnancy, it is expect-ed that the combination will also be safe, but this has not been formally evaluated in pregnant women (Winstanley, 2001). Lapdap was well tolerated in a study of single doses in pregnant women in western Kenya, but specific monitoring for adverse fetal out-comes was not conducted (Keuter et al., 1990).

In addition to confirmation of the safety of the fixed combination, another key question is the efficacy of this short-acting antimalarial when used as IPT. SP is a long-acting antimalarial providing effective treatment of existing infections as well as providing 3–4 weeks of protection against new infections in persons living in areas where the disease shows no or limited resistance to SP. Thus, two or more doses of SP during pregnancy provide prolonged periods of chemoprophylaxis during the second and third trimester. It is unknown whether this long-term pro-tection is essential or if short-acting drugs that rap-idly clear parasites from the placenta but do not provide sustained protection, such as Lapdap, will be equally effective (Greenwood, 2001). Even if the combination is not as effective as IPT, it is likely to prove very useful in the case management of malar-ia in pregnancy, as it has shown good efficacy in the second-line treatment of cases for which treatment with SP has failed (Mutabingwa et al, 2001).

Table 3. Possible regimens for antimalarial drugs used for treatment and prophylaxis of malaria in pregnancy From Newman et al. (2003)

Drug Intermittent preventive treatment (IPT)* Chemoprophylaxis

Sulfadoxine 25 mg-pyrimethamine 500 mg (SP) 3 tablets as a single dose Not recommended

Chloroquine 25 mg of base per kg total, in divided doses over 3 days 300 mg base weekly

Amodiaquine 30 mg of base per kg total, in divided doses over 3 days (safety in pregnancy not established)

Not recommended

Amodiaquine + SP Amodiaquine as above + SP as above(safety in pregnancy not established)

Not recommended

Chlorproguanil 80 mg + dapsone 100 mg (Lapdap)

Chlorproguanil at 2 mg/kg, daily for 3 days + dapsone at 2.5 mg/kg, daily for 3 days(safety in pregnancy not established)

No available data

Sulfadoxine-pyrimethamine + artesunate SP as above + artesunate at 4 mg/kg, daily for 3 days total in divided doses over 3 days (safety in pregnancy not established)

Not recommended

Artemether 20 mg; lumefantrine 120 mg (Riamet, Coartem)

4 tablets at 0 h, 8 h, 24 h, and 48 h or4 tablets at 0 h, 8 h, 24 h, 36 h, 48 h, and 60 h(safety in pregnancy not established)

Not recommended

Chlorproguanil + dapsone + artesunate Dose not yet determined(safety in pregnancy not established)

Not recommended

Amodiaquine + artesunate Amodiaquine as above + artesunate as above(safety in pregnancy not established)

Not recommended

Pyrimethamine 12.5 mg; dapsone 100mg (Maloprim)

Not recommended 1 tablet weekly

Atovaquone 250 mg; proguanil 100 mg (Malarone)

4 tablets daily for 3 days (safety in pregnancy not established)

1 tablet daily (safety in pregnancy not established)

Mefloquine 15 mg base/kg as a single dose; or 25 mg/kg divided as two doses 6–8 h apart

5 mg base/kg weekly (usually 250 mg or 1 tablet)

Mefloquine + artesunate Mefloquine as above + artesunate as above(safety in pregnancy debated)

Not recommended

Azithromycin Not recommended 250 mg daily (safety for this use not established)

Proguanil + chloroquine Not recommended Proguanil 200 mg daily + chloroquine prophylaxis as above

* Frequency at which the regimen is repeated during pregnancy may vary.


3.3 Artemisinins and combination therapy containing artemisinins

Combinations of SP plus artesunate, amodiaquine-artesunate, lapdap-artsunate, and artemether-lume-fantrine (below) are all potential alternatives to monotherapy with SP. The participants at two WHO meetings to review the preclinical (animal) data and limited data in humans on use of artemisinin com-pounds in pregnancy concluded that these drugs have a good safety profile, particularly in the second and third trimesters of pregnancy and during lacta-tion. The information on women treated in the first trimester is sparse and hence the drug should only be used in life-saving circumstances in this trimester (severe malaria) (McGready, 2002). Careful follow-up of pregnant women exposed to any antimalari-al, including artemisinin compounds for treatment (or intermittent preventive treatment), and the sub-sequent development of the child, should be doc-umented to guide further development of policies on the use of artemisinin derivatives in pregnancy (Nosten & McGready, 2001). To date, no studies eval-uating artemisinins for IPT during pregnancy have been undertaken, although an evaluation of com-bination therapy with an artemisinin and SP dur-ing pregnancy is planned for the United Republic of Tanzania (MacArthur J, personal communication).

3.4 Artemether-lumefantrine (Riamet, Co-artem)

There are no studies evaluating artemether-lume-fantrine in pregnant women. In general, the safety of this combination has been good in both children and adults (von Seidlein et al., 1997; van Vugt et al., 1999). Efficacy in the treatment of adults with mul-tidrug-resistant P. falciparum has also been good; six doses given over 5 days appears more effective than four doses given over 3 days (van Vugt et al., 1999; Lefevre et al., 2000). A Cochrane systematic review concluded that the combination was more effective than chloroquine, but less effective than mefloquine or mefloquine-artesunate in treating uncomplicated falciparum malaria, and that no conclusion could be reached regarding comparison with SP (Omari et al., 2002). Second episodes of malaria within 4 weeks were more common in Gambian children treated with artemether-lumefantrine than with SP, sug-gesting that the prophylactic window of protection is shorter than with SP (von Seidlein et al., 1998).

4. PREVENTION OF VIVAX MALARIA

Vivax malaria was recently shown to be associat-ed with reduced birth weight and increased mater-nal anaemia, although the magnitude of effect is lower than with P. falciparum (Nosten et al., 1999;

Singh et al, 1999). Unlike P. falciparum, P. vivax is not known to be sequestered in the placenta, suggest-ing that other pathophysiological processes are the cause of the adverse impact on the fetus, such as a shift from type-2 towards type-1 cytokine-response (Nosten et al., 1999). Confirmation of these findings in studies outside of Asia is needed. Further explo-ration of interventions to prevent vivax malaria in these settings, including the role of chloroquine, as prophylaxis or IPT, are required. No information is available on the adverse effects of P. ovale or P. malar-iae in pregnancy. Their treatment and prevention also rely on chloroquine.

5. METHODS OF ASSESSMENT OF ANTIMALARIALS

Assessing the efficacy of an antimalarial in preg-nancy is difficult. The interpretation of clearance of peripheral parasitaemia is problematic because par-asites can escape drug action by harbouring in the placenta. Studies in Thailand indicate that parasites are cleared from the peripheral blood after treat-ment but can re-emerge 2 months later (Nosten & McGready, 2001). Standardized guidelines assessing the response to treatment with antimalarials for case management, as well as IPT, are required.

6. INSECTICIDE-TREATED BEDNETS

It was shown recently that the reason why preg-nant women are more vulnerable to malaria than non-pregnant women might be partly because preg-nant women are more attractive to Anopheles gambiae mosquitoes (Lindsay et al., 2000). Preventive mea-sures to reduce bites by infected mosquitoes, includ-ing the use of ITNs, are an important potential tool in the control of malaria in pregnancy.

To date, six randomized, controlled studies have been conducted to determine the impact of use of bednets in pregnancy and one non-randomized study of the effect of socially marketed ITNs (D’Alessandro et al., 1996; Shulman et al., 1998; Shulman et al., 1999; Browne et al., 2001; Marchant et al., 2002; ter Kuile et al., 2003a). These studies cover a wide spectrum of malaria endemicity, ranging from stable, low transmission, to high and markedly seasonal malar-ia transmission, to intense perennial transmission. The first four studies showed that in areas with the lowest and most seasonal transmission (Thailand and the Gambia) ITNs significantly reduced malaria parasitaemia and maternal anaemia, and increased birth weight (Dolan et al., 1993; D’Alessandro et al., 1996), but no impact was observed in areas with higher transmission (coastal Kenya, and Ghana) (Shulman et al., 1998; Browne et al., 2001) (Table 4).


Tabl

e 4.

Stu

dies

of i

nsec

tici

de-t

reat

ed b

edne

ts u

sed

in p

regn

ancy

Stud

y, c

ount

ryTr

ansm

issi

on(E

IR)

Cont

rol

grou

pN

o. o

f IT

N,

No.

of

cont

rols

Com

men

tsAn

aem

iaa

Seve

rean

aem

iab

Mat

erna

lm

alar

iaPl

acen

tal

mal

aria

Low

bir

th

wei

ght

(g)

Dola

n et

al.

(199

3), T

haila

ndLo

w(<

1)

No n

et11

111

8Al

l gra

vida

e, c

ontr

ol (

N =

30, n

o ne

t)An

tena

tal c

are

clin

ic-b

ased

rand

omiz

atio

nPR

: 0.5

NAPR

: 0.5

1NA

PR: 0

.64

D’ A

less

andr

o et

al.

(199

6), T

he G

ambi

aLo

wse

ason

al(1

–10)

No n

et o

r un

trea

ted

305

341

Prim

igra

vida

eRa

iny

seas

onNA

PR: 1

.18

PR: 0

.61

NA+

130

g

Dry

seas

onNA

PR: 0

.32

PR: 1

.11

NA-

135

g

Shul

man

et

al. (

1998

), K

enya

Inte

rmed

iate

seas

onal

(10–

30)

No n

et26

322

8Pr

imig

ravi

dae,

Vi

llage

-bas

ed ra

ndom

izat

ion

Hosp

ital

ant

enat

al c

are

clin

ic a

tten

dees

PR: 0

.99

OR: 0

.71

OR: 0

.75

OR: 0

.75

0 g

Brow

ne e

t al

. (20

01),

Ghan

aH

igh

seas

onal

(300

)

No n

et10

33 928

All g

ravi

dae,

Hous

ehol

d, c

hild

ren

aged

< 5

yea

rsOR

: 0.8

8OR

: 0.8

0OR

: 0.8

9NA

OR: 0

.87

ter K

uile

et

al. (

2003

a), K

enya

Hig

hpe

renn

ial

(100

–300

)

No n

et13

7713

77

All g

ravi

dae

Grav

idae

1–4

HR:

0.7

9cH

R: 0

.70c

PR: 0

.62

PR: 0

.77

PR: 0

.78

+ 78

g

Grav

idae

≥ 5

HR:

1.0

0cH

R: 1

.24c

PR: 0

.80

PR: 0

.72

PR: 1

.12

- 27

g

Njag

i (20

02),

Ken

yaH

igh

pere

nnia

l(1

00–3

00)

No n

et48

048

3Pr

imi+

secu

ndi g

ravi

dae

Ante

nata

l car

e cl

inic

-bas

ed ra

ndom

izat

ion

PR: 0

.69

NAPR

: 0.7

0PR

: 0.6

1PR

: 0.6

8+

67 g

Mar

chan

t et

al.

(200

2),

Unit

ed R

epub

lic o

f Tan

zani

aH

igh

pere

nnia

l(1

00–3

00)

No n

et23

926

6Al

l gra

vida

e, n

on-r

ando

miz

ed,

soci

al m

arke

ting

RR: 0

.88

RR: 0

.62

RR: 0

.77d

NANA

Bold

face

refle

cts

stat

isti

cally

sig

nific

ant

diff

eren

ces.

NA

, not

app

licab

le

PR, p

reva

lenc

e ra

tio;

OR,

odd

s ra

tio;

RR,

risk

rati

o; H

R, h

azar

d ra

tio.

EI

R, e

ntom

olog

ical

inoc

ulat

ion

rate

a Any

ana

emia

(ha

emog

lobi

n, <

11

or 1

0 g/

dl, o

r hae

mat

ocrit

, < 3

0%)

b Sev

ere

anae

mia

(ha

emog

lobi

n, <

8 o

r 7 g

/dl)

c Gra

vida

e 1–

4, N

= 4

51; g

ravi

dae ≥

5, N

= 3

13.

d Sig

nific

ant

redu

ctio

n in

hig

h de

nsit

y pa

rasi

taem

ia, R

R, 0

.62

(95%

CI,

0.4

1–0.

95)


Thus, although the number of studies were limited, it is tempting to hypothesize that the impact of bed-nets decreases with the intensity of malaria trans-mission, and that in higher-transmission settings or where there are prolonged seasons of P. falciparum transmission, ITNs alone do not prevent the adverse effects of malaria in pregnancy (Shulman et al., 1998; Mutabingwa et al., 2001; ter Kuile et al., 2003a). However, results, from the two recently-completed randomized, controlled trials in areas with intense perennial malaria transmission in western Kenya and the non-randomized study of socially marketed ITNs in southern United Republic of Tanzania, do not support this hypothesis (Table 4) (Marchant et al., 2002; Njagi, 2002; ter Kuile et al., 2003a).

6.1 Gaps in knowledge

Mass effect versus individual barrier protection

Four of the six randomized studies were group-ran-domized trials, with the village as the randomiza-tion unit. Two studies assessed the effect of ITNs when distributed as part of antenatal care. The effect of ITNs in group-randomized trials reflects the combined effects of individual barrier protection as well as area-wide reductions in malaria trans-mission (‘community’ or ‘mass’ effect). Individuals using ITNs in areas with low ITN coverage do not benefit from this community effect. This con-cept may be important in the interpretation of the available studies of use of ITNs in pregnancy. It is likely that the mass killing effect on mosquito pop-ulations will have resulted in an underestimate of the impact of ITNs on malaria in pregnancy in the group-randomized trials. The KEMRI/CDC bednet trial in western Kenya suggested that the commu-nity effect can be substantial, and that adjustment for this effect increased the estimates of efficacy rel-ative to childhood morbidity by between 7% (clini-cal malaria) and 20% (haemoglobin concentrations) (Hawley et al., 2003). The study by Dolan and col-leagues may be difficult to interpret in this respect, as women randomized to the different study groups lived in the same very densely populated refugee camps (Dolan et al., 1993). Extrapolation of results from group-randomized trials to predict the impact in programmes that distribute ITNs to individual pregnant women, or vice versa, should be done with care. The study by Njagi and colleagues, which used simple randomization by individual, is unique as it was conducted in an area with low ITN coverage (little “mass” effect). Results suggest that ITNs dis-tributed to individual women as part of antenatal care are effective (Njagi et al., 2002).

Intermittent preventive treatment plus insecti-cide-treated nets

Multi-pronged, redundant systems approach-es to malaria control may be most likely to suc-ceed (McKenzie et al., 2002). Additional studies are required to delineate the role of individual versus community effect and the impact and cost–effective-ness of programmes to control malaria in pregnan-cy that use single interventions versus programmes that combine the benefits of IPT and ITN use, dis-tributed either as part of community-based pro-grammes or through antenatal clinics. Only one study has assessed the combined effect of IPT with ITNs using a factorial design (Njagi, 2002). This study showed that both interventions are effective, but IPT had a greater impact on maternal anaemia than ITN, and little additional benefit was obtained by combining IPT and ITNs.

This randomized study distributed ITNs in the sec-ond trimester as part of antenatal care. It is unknown if these results apply to population-based ITN pro-grammes, which have the advantage of protecting women prior to, as well as throughout pregnan-cy (and mother and child in the post-partum peri-od). There is a dearth of information on the impact of malaria control in early pregnancy. The risk of peripheral malaria parasitaemia is greatest in the first 20 weeks of gestation, with rates of malar-ia infection at delivery approximating those in the postnatal period and those seen in non-pregnant women. The combined effects of short-acting anti-malarials, such as Lapdap, and ITN also deserve further consideration.

Adherence

High compliance with use of bednets by pregnant women has been observed in most studies ( Dolan et al., 1993; Browne et al., 2001; ter Kuile et al., 2003a). Adolescence, not married or cohabiting, and first pregnancy were the main factors associated with low compliance (Browne et al., 2001; Marchant et al., 2002; ter Kuile et al., 2003a) reinforcing the need to improve health education strategies in this high-risk age group, possibly using school-based (pre-preg-nancy) approaches. Low compliance may be a great-er determinant of efficacy when nets are distributed to individual pregnant women as part of packages from antenatal care clinics than in population-based programmes that benefit from a mass effect.

Improving coverage with insecticide-treated bednets

There a need to device operational studies defin-ing appropriate strategies to improve coverage of


ITNs (with and without IPT) in pregnant women and their infants, e.g. by combining antenatal care programmes with maternal and child-health pro-grammes. ITNs could be distributed at antenatal clinics, re-impregnated at one of the first visits for childhood immunization/IPT for infants, and again at the time of vaccination for measles.

Who should be targeted?

Because the effects of malaria in areas where it is endemic are most marked in primi- and secundi-gravidae, control interventions might be restricted to these high-risk pregnancies. There are several argu-ments in favour of targeting all pregnant women, regardless of their parity. First, three out of four studies that included women of all pregnancy order showed that the benefits of ITN extend beyond primi and secundi-gravidae and include women of higher pregnancy order. Second, most areas in which malaria is endemic also have a high or increasing prevalence of infection with HIV. HIV is known to impair the ability of the pregnant woman to con-trol malaria (especially among the older multi-grav-idae; Steketee et al., 1996), to aggravate the adverse effects of malaria on maternal anaemia and pregnan-cy outcome in women of all pregnancy order (Ayisi et al., 2003), and to reduce the efficacy of intermit-tent preventive treatment (Parise et al., 1998). Third, reducing exposure to malaria in the first pregnan-cy might prevent the development of the specific immune response to sequestering parasites (Fried & Duffy, 1996), transferring the risk to future preg-nancies. Similar considerations apply to areas with very low transmission, such as in parts of south-east Asia (Greenwood, 2001). Fourth, in many develop-ing countries targeting younger pregnancies may create ill-feeling among non-participating individ-uals, affecting the popularity of the programme (Mutabingwa et al., 2001). Fifth, and probably most important; if mothers continue to use the ITN post-partum, newborns that share the sleeping space with their mothers will likely benefit from reduced exposure to malaria in the first few months of life (ter Kuile et al., 2003b). Lastly, targeting all high-risk pregnancies, rather than a selected group, will increase coverage and contribute to any community effect on malaria transmission (Gimnig et al., 2003), and the likelihood of attaining the target of 60% cov-erage of high-risk groups, stated in the Abuja decla-ration (WHO, 2000b).

7. OTHER PROTECTIVE MEASURES

7.1 Insect repellents

Insect repellents containing N,N-diethyl-m-tolu-amide (DEET) have recently proved effective in

reducing exposure of pregnant women to Anopheles mosquitoes (Lindsay et al., 1998). The risk of DEET accumulating in the fetus is low and DEET is safe to use in later pregnancy (McGready et al., 2001a). One randomized controlled trial of insect repellents (20% diethyl-benzamide) for the prevention of malaria in pregnancy showed a non-significant reduction by 28% in the incidence of falciparum malaria, in an area of very low malaria transmission on the bor-der between Thailand and Myanmar (McGready et al., 2001b). No studies have been conducted in areas where transmission is more intense.

Disclaimer: The opinions or assertions contained in this man-uscript are those of the authors and are not to be construed as reflecting the official views of the US Public Health Service or Department of Health and Human Services. Use of trade names is for identification only and does not imply endorse-ment by US Public Health Service or Department of Health and Human Services.

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Annex 5 WORKING PAPER: New and improved antimalarial drugs


NEW AND IMPROVED ANTIMALARIAL DRUGS

Sornchai LooareesuwanDepartment of Clinical Tropical Medicine Faculty of Tropical MedicineMahidol UniversityBangkok, Thailand

1. INTRODUCTION

With the emergence of multidrug-resistant falci-parum malaria, new drugs and drug combinations are urgently needed. A drug-discovery approach to the search for new antimalarial drugs could include seeking third-generation combinations of antifolate drugs, and inhibitors of P. falciparum merozoite sur-face protein-1 (MSP-1) processing protease, fatty acid biosynthesis, lactate dehydrogenase, phospho-lipid metabolism or protein farnesyltransferase. However, it may take more than 5 years to discov-er one new antimalarial drug. In contrast, the time required to develop antimalarial drugs may be shorter (3–5 years). This approach could include the development of intravenous artemisinin derivatives and artesunate suppositories for the treatment of severe malaria, and development of a fixed com-bination of artesunate-chlorproguanil-dapsone, an artesunate-sulfadoxine/pyrimethamine, a dihydro-artemisinin-piperaquine combination, or an arte-sunate-pyronaridine combination, development of a synthetic endoperoxide, and development of iso-quine (4-aminoquinoline) for treatment of uncom-plicated malaria.

This paper describes some of the new antimalari-al drugs under investigation at the Hospital for Tropical Diseases, Bangkok, and in use in Thailand.

2. NEW ANTIMALARIAL DRUG TRIALS

New antimalarial drugs that have been investigated in recent years at the Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, include the following:

2.1 Atovaquone

Atovaquone, a hydroxynaphthoquinone, has been evaluated and found to be safe and effective when used alone. All patients treated were clinically cured, however, one-third of patients had late recru-descence (RI). When atovaquone was combined with proguanil, the cure rate increased to 100%. This

combination has now been developed into a fixed drug combination named Malarone®.

2.2 Artemisinin derivatives

Artemisinin derivatives such as artesunate, arte-mether, arteether and dihydroartemisinin have also been tested at the Hospital for Tropical Diseases. Artesunate and artemether alone at a total dose of 600–750 mg, given over 5–7 days, produced cure rates of 80–95%. Artesunate or dihydroartemisinin suppositories given at a dose of 10 mg/kg bw per day have proved successful in the treatment of severe malaria. The combination of artemisinin derivatives (at a dose of 4 mg/kg of body weight per day) and mefloquine (at a dose of 8 mg/kg of body weight per day), given once a day for 3 days, gave improved cure rates of up to 95–100%. Dihydroartemisinin, at a total dose of 480 mg given over 5 days, produced a cure rate of 90%. Arteether, a drug whose devel-opment was supported by TDR, has been evaluated in the Hospital and has now been registered for use in severe malaria (at the same dose as that for arte-mether), under the name of Artemotil®. Other com-binations (artemisinin derivatives combined with tetracycline or doxycycline, and mefloquine com-bined with tetracycline or doxycycline) have also been evaluated and shown to produce improvement in cure rates. Recently, a fixed drug combination containing artemether plus lumefantrine (Coartem®) given in six doses over 72 hours has proved to be a safe and effective drug for the treatment of falci-parum malaria, producing cure rates of over 95%, and it has been registered for use in many industri-alized countries.

At present, studies are underway to investigate combinations of artemisinin derivatives plus meflo-quine (at various doses and durations of treatment). We have recently completed a double-blind, ran-domized, comparative study of 200 patients (adults and children) with falciparum malaria treated with artesunate, 4 mg/kg of body weight per day and mefloquine, 8 mg/kg of body weight per day, given once a day for 3 days, in pre-packed blister packs. We found that this approach proved safe and effec-tive and could translate clinically into better patient compliance. Other fixed combinations (Artecom®, Artekin®) have proved safe and efficacious (cure rate over 98%) and could be alternative antimalarial drugs. In general, artemisinin derivatives (at a total dose of 12 mg/kg of body weight, given over 3 days) combined with mefloquine (at a total dose of 25 mg/kg of body weight, given over 3 days) have been a standard regimen for the treatment of multidrug-resistant falciparum malaria in Thailand. Until the evidence suggests a change in practice, drug com-


binations are still recommended for the treatment of all adult patients suffering from acute uncomplicat-ed falciparum malaria contracted in areas in which multidrug resistance is found.

3. MANAGEMENT OF MALARIA

Treatment for uncomplicated malaria aims to pro-duce a radical cure using one of the following com-binations: – Artesunate (4 mg/kg of body weight per day)

plus mefloquine (8 mg/kg of body weight per day) for 3 days;

– A fixed dose of artemether plus lumefan-trine called Coartem® (4 tablets containing 20/120 mg, respectively, twice a day for three days, for adults weighing more than 35 kg);

– Quinine at a dose of 10 mg/kg of body weight every 8 hours, plus tetracycline at a dose of 250 mg every 6 hours for 7 days (or, as an alter-native to tetracycline, doxycycline at a dose of 200 mg once a day for 7 days) in patients aged 8 years and above; and

– A combination of 250 mg atovaquone and 100 mg proguanil called Malarone® (in adults, 4 tablets given daily for 3 days).

In treating severe malaria, early diagnosis and early treatment with a potent antimalarial drug is recom-mended to save the patient’s life. The antimalarial drugs of choice are: – Intravenous quinine or a parenteral form of

an artemisinin derivative (artesunate by intra-venous/intramuscular injection at a dose of 2.4 mg/kg of body weight, followed by a dose of 1.2 mg/kg of body weight at 12 and 24 hours, and then 1.2 mg/kg of body weight daily for 5 days;

– Artemether by intramuscular injection at a dose of 3.2 mg/kg of body weight, followed by 1.6 mg/kg of body weight at 12 and 24 hours and then 1.6 mg/kg of body weight daily for 5 days;

– Arteether by intramuscular injection (Artemotil®), at the same dose as for artemether;

– Artesunate suppository (5 mg/kg of body weight) given at 12-hour intervals for 3 days.

Oral artemisinin derivatives (artesunate, artemether, dihydroartemisinin, at a dose of 4 mg/kg of body weight per day) should replace parenteral forms when patients can tolerate oral medication. Oral mefloquine (at 25 mg/kg of body weight divided into two doses, given with an interval of 8 hours between doses) should be administered at the end of the course of treatment with artemisinin to reduce recrudescence.

Chloroquine and primaquine are still used for the treatment of vivax malaria in Thailand. However in cases in which primaquine is ineffective at the usual dose (15 mg/kg of body weight per day for 14 days, with a relapse rate of 15%), the higher dose (30 mg/kg of body weight per day for 14 days) is recom-mended. Studies of the efficacy of primaquine in various regimens, given in combination with sulf-adoxin/pyrimethamine or artemisinin derivatives, are in progress. A phase III study with Tafenoquine®, in preparation for clinical trials in Thailand, is in progress.

References on which this text is based

Buchachart K et al. Effect of primaquine standard dose (15 mg/day for 14 days) in the treatment of vivax malaria patients in Thailand. Southeast Asian Journal of Tropical Medicine and Public Health, 2001, 32(4):720–726.

Krudsood S et al. A comparative clinical trial of com-binations of dihydroartemisinin plus azithromycin and dihydroartemisinin plus mefloquine for treatment of multidrug resistant falciparum malaria. Southeast Asian Journal of Tropical Medicine and Public Health, 2002, 33(3):525–531.

Krudsood S et al. An open randomized clinical trial of artekin® vs artesunate-mefloquine in the treatment of acute uncomplicated falciparum malaria. Submitted 2004.

Krudsood S et al. Comparative clinical trial of two-fixed combinations dihydroartemisinin–napthoquine- trimethoprim (DNP®) and artemether-lumefantrine (Coartem®/ Riamet®) in the treatment of acute uncom-plicated falciparum malaria in Thailand. Southeast Asian Journal of Tropical Medicine and Public Health, 2003, 34(2):316–321.

Krudsood S et al. Artesunate and mefloquine given simultaneously for three days via a prepacked blis-ter is equally effective and tolerated as a stand-ard sequential treatment of uncomplicated acute Plasmodium falciparum malaria: randomized, double-blind study in Thailand. American Journal of Tropical Medicine and Hygiene, 2002, 67(5):465–472.

Looareesuwan S et al. Primaquine-tolerant vivax malaria in Thailand. Annals of Tropical Medicine and Parasitology, 1997, 91(8):939–43.

Looareesuwan S et al. Clinical study of pyronaridine for the treatment of acute uncomplicated falciparum malaria in Thailand. American Journal of Tropical Medicine and Hygiene, 1996, 54(2):205–9.


Looareesuwan S et al. Dose-finding and efficacy study for i.m. artemotil (beta-arteether) and comparison with i.m. artemether in acute uncomplicated P. falci-parum malaria. British Journal of Clinical Pharmacology, 2002, 53:492–500.

Looareesuwan S et al. Randomised trial of meflo-quine-tetracycline, and quinine-tetracycline for acute uncomplicated falciparum malaria. Acta Tropica, 1994, 57:47–53.

Looareesuwan S et al. Randomised trial of meflo-quine-doxycycline, and artesunate-doxycycline for treatment of acute uncomplicated falciparum malaria. American Journal of Tropical Medicine and Hygiene, 1994, 50(6):784–9.

Looareesuwan S et al. Comparative clinical trial of artesunate followed by mefloquine in the treatment of acute uncomplicated falciparum malaria: two and three-day regimens. American Journal of Tropical Medicine and Hygiene, 1996, 54(2):210–3.

Looareesuwan S et al. Randomized trial of artesuna-te and mefloquine alone and in sequence for acute uncomplicated falciparum malaria. The Lancet, 1992, i:821–4.

Looareesuwan S et al. A randomized, double-blind, comparative trial of a new oral combination of arte-mether and benflumetol (CGP 56697) with mefloquine in the treatment of acute Plasmodium falciparum malar-ia in Thailand. American Journal of Tropical Medicine and Hygiene, 1999, 60(2):238–43.

Looareesuwan S et al. Atovaquone and proguanil hydrochloride followed by primaquine for treatment of Plasmodium vivax malaria in Thailand. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1999, 93:637–40.

Looareesuwan S, et al. A comparative clinical trial of sequential treatment of severe malaria with artesuna-te suppository followed by mefloquine in Thailand. American Journal of Tropical Medicine and Hygiene, 1997, 57(3):348–53.

Looareesuwan S et al. Monotherapy with artesuna-te for uncomplicated falciparum malaria: A compar-ison of 5-day and 7-day regimens. Acta Tropica, 1997, 67:197–205.

Looareesuwan S et al. Treatment of acute uncompli-cated falciparum malaria with oral dihydroartemisi-nin. Annals of Tropical Medicine and Parasitology, 1996, 90(1):21–8.

Looareesuwan S et al. Efficacy and tolerability of a sequential, artesunate suppository plus mefloquine, treatment of severe falciparum malaria. Annals of Tropical Medicine and Parasitology, 1995, 89(5):469–75.

Looareesuwan S et al. Clinical studies of atovaquone, alone or in combination with other antimalarial drugs, for treatment of acute uncomplicated malaria in Thailand. American Journal of Tropical Medicine and Hygiene, 1996, 54(1):62–6.

Mason DP et al. Can treatment of P. vivax lead to a unexpected appearance of falciparum malaria? Southeast Asian Journal of Tropical Medicine and Public Health, 2001, 32(1):57–63.

Myint Hy et al. A systematic overview of published antimalarial drug trials. Transactions of the Royal Society of Tropical Medicine and Hygiene, 2004, 98:73–81.

Nosten F et al. Effects of artesunate-mefloquine com-bination on incidence of Plasmodium falciparum malar-ia and mefloquine resistance in western Thailand: a prospective study. The Lancet, 2000, 356:297–302.

Pongponratn E et al. Absence of knobs on parasitized red blood cells in a splenectomized patient in fatal fal-ciparum malaria. Southeast Asian Journal of Tropical Medicine and Public Health, 2000, 31(4):829–835.

Pukrittayakamee S et al. Therapeutic responses to antibacterial drugs in vivax malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 2001, 95:524–528.

Silachamroon U et al. Clinical trial of oral artesuna-te with or without high-dose primaquine for the treat-ment of vivax malaria in Thailand. American Journal of Tropical Medicine and Hygiene, 2003, 69(1):14–18.

Walsh DS et al. Randomized dose-ranging study of the safety and efficacy of WR 238605 (Tefenoquine) in the prevention of relapse of Plasmodium vivax malar-ia in Thailand. Journal of Infectious Diseases, 1999, 180:1282–7.

Westerlund EK et al. Predicting mortality in patients with malarial acute renal failure. Nephrology, 2000, 5:1–2, 109–113.

Wilairatana P et al. A comparison of three different dihydroartemisinin formulations for the treatment of acute uncomplicated falciparum malaria in Thailand. International Journal for Parasitology, 1998, 28(8):1213–8.

Wilairatana P et al. An open randomized clinical trial of artecom® vs artesunate-mefloquine in the treat-ment of acute uncomplicated falciparum malaria in Thailand. Southeast Asian Journal of Tropical Medicine and Public Health, 2002, 33(3):519–524.

Wilairatana P et al. A clinical trial of combination of artesunate and mefloquine in the treatment of acute uncomplicated falciparum malaria: a short and practi-cal regimen. Southeast Asian Journal of Tropical Medicine and Public Health, 1998, 29(4):696–701.


Wilairatana P et al. Clinical trial of sequential treat-ments of moderately severe and severe malaria with dihydroartemisinin suppository followed by meflo-quine in Thailand. American Journal of Tropical Medicine and Hygiene, 2000, 63(5,6):290–4.

Wilairatana P et al. Poor efficacy of antimalarial biguanide-dapsone combinations in the treatment of acute, uncomplicated, falciparum malaria in Thailand. Annals of Tropical Medicine and Parasitology, 1997, 9(2):125–32.

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Annex 6 WORKING PAPER: Insecticide-treated nets – implementation strategies


INSECTICIDE-TREATED NETS: IMPLEMENTATION STRATEGIES

Jo LinesLondon School of Hygiene and Tropical Medicine Department of Medical ParasitologyKeppel StreetLondon WC1E 7HTUnited Kingdom

1. INTRODUCTION

The Roll Back Malaria programme has recently pub-lished a ‘strategic framework’1 to guide attempts to scale up coverage of insecticide-treated nets (ITNs) in Africa. The intention of this paper is not to detail the arguments and recommendations discussed in this publication, but to explain very briefly how and why the document was developed, and to outline some of the most important research issues raised by the ITN strategic framework.

2. ISSUES CONCERNING IMPLEMENTATION STRATEGIES FOR INSECTICIDE-TREATED NETS

Implementation strategies for ITNs have been the subject of debate and of divergent public health per-spectives ever since ITNs started to be used in rou-tine projects for the control of malaria, about 10–12 years ago. At the heart of this prolonged controver-sy are three practical questions that are faced by all ITN projects and programmes: how should ITNs be distributed, how should this be financed, and who should receive them? These are separate, but obvi-ously connected, issues. For example, public sector health systems are generally subsidized, and gener-ally strive to give universal provision, while commer-cial distributors of textiles and domestic insecticides are generally not subsidized, and survive by selling to those who are able and willing to pay.

Mixed up with these practical choices, therefore, are issues related to the purpose of the whole exercise: sustainability, equity, and coverage. For example, the commercial sector is self-financing and hence sustain-able, but it carries no guarantee of either high cover-age or of equity. Conversely, giving away nets and insecticide free of charge to everyone would provide complete equity and coverage, but is not sustainable without a massive increase in donor aid flows.

This leads naturally to the question of whether a

combined approach might allow us to maximize the advantages, and minimize the disadvantages, of several different distribution systems. However, the ability to do this is constrained by the competition that must be expected when the same goods are sup-plied to the same people by two different distribu-tion systems. People who have access to good quality nets, supplied free of charge or at a cheap price by a subsidized distribution system, are unlikely to buy more expensive nets from the unsubsidized com-mercial market. Consequently, commercial traders are likely to sell less than they otherwise would, and may be displaced from the market. Thus, if nothing is done to limit this problem, setting up a subsidized supply system could “crowd out” the unsubsidized commercial system.

Faced with these constraints and trade-offs, many early ITN implementation projects adopted “com-promise” strategies. They chose to sell ITNs, rather than give them away for free, but did so at subsi-dized prices. Income from sales was invested in a “revolving fund” that was to be used to buy replace-ment stock, and thus provide sustainability. In many cases, the ITNs were sold at a “cost recovery” price, i.e. close to the price at which the project bought nets from the factory. Thus, in effect, the user paid for the materials, and the project subsidy paid for the oper-ational costs of procurement, transport, storage, and selling.

It was generally assumed that selling ITNs rather than giving them away would reduce the project’s long-term dependence on subsidy. This is not neces-sarily so; selling entails a variety of additional activ-ities, such as promotion of demand, and collecting and handling the money from sales, which are not needed when ITNs are given away free of charge. It is not hard to imagine circumstances in which these additional costs might exceed the income from sales. This point has recently been illustrated in Kenya, when 70 000 nets were distributed free of charge to pregnant women attending antenatal care clinics. When the exercise was evaluated after a few months, 53% of these nets had been received by a pregnant woman, about one-quarter were still in store or in transit, and the remainder had been lost or given to someone other than a pregnant woman. The overall cost, allowing for these losses, was esti-mated as about US$ 5.20 per net received by a preg-nant woman. This may be compared with some costs collected by the Malaria Consortium from projects that have sold nets at “material-cost-recovery” pric-es. These projects adopted a variety of distribution systems (including three product-based social mar-

1 Roll Back Malaria (2002) Scaling-up insecticide-treated netting programmes in Africa: a strategic framework for coordinated national action. Geneva, World Health Organization (WHO/CDS/RBM/2002.43; http://rbm.who.int/cmc_upload/0/000/015/845/itn_programmes.pdf).


keting projects, employer-based distribution, and the United Nations Children’s Fund (UNICEF)-style local revolving fund systems). In one case, the cost per net delivered (calculated as the overall cost to the donor, divided by the number of nets sold) was less than US$ 4. In six other cases, it ranged from US$ 6 per net to more than US$ 20 per net.

Of course, these are very crude figures, which are calculated in different ways, and take no account of the longer-term health-development benefits that are among the aims of some of the more expensive projects. More and better information on operational costs and cost–effectiveness of different implementa-tion approaches is clearly needed. Very few routine implementation projects (as opposed to research tri-als) have reported their costs at all, and those that have done so have often used different assumptions and methods of calculation. In particular, we lack estimates of the cost of giving away ITNs free of charge, as opposed to selling them, and estimates of the additional cost of targeting nets (whether given or sold) to a particular subgroup (such as pregnant women) rather than making them openly available or covering the entire local population. It would be beneficial if economists could suggest a reason-ably simple and standardized system for estimat-ing costs, and an agency were to be charged with the task of collating this information.

Meanwhile, there has been increasing recognition that, in some parts of Africa, private sector markets in untreated nets support levels of coverage that, while they are usually well short of public health tar-gets, are nevertheless of considerable public health value. Demographic and Health surveys (DHS) and UNICEF’s Micro-Indicator Cluster surveys (MICS) have made a key contribution in this respect. Some of these data must have surprised some implementing agencies that previously believed that commercial markets for nets served only the urban rich. The data showed, for example, that coverage in Timbuktu – a small town in central Mali, and a byword for remote isolation – is about 85%. While in many cases there is indeed higher coverage in urban than in rural areas, and among the rich than among the poor, coverage among the rural poor is far from negligible. To some extent, one’s attitude to these figures is a matter of interpretation: should one be pleased that the cup is half full, or disappointed because it is half empty? In the United Republic of Tanzania, for example, more than 20% of rural households have at least one net, compared to less than 5% a few years ago.

There is some evidence that socioeconomic inequi-ty tends to decline as coverage increases. Should we value this achievement, and try to build on it, or should we be disappointed, and conclude that the private sector has little public health value, because urban coverage is about three times higher? In any case, we certainly should be pleased that this kind of data on national-level coverage are now becom-ing available, and we should try to collect more of it, more often.

These data also illustrate another gap in our knowl-edge. Whereas we have a great deal of carefully col-lected information on the effectiveness of ITNs as a means of malaria control, much less effort has been devoted to measuring the protection against malar-ia given by untreated nets. This seems inappropri-ate when the great majority of nets currently used in Africa are untreated, and are likely to remain so for some years to come. In the absence of clear and decisive evidence, some planners assume that these untreated nets are more or less useless, while oth-ers prefer to believe recent data suggesting that they give a significant, if reduced, level of protection; this question needs to be resolved. A related question is the residual duration of epidemiological protection. It is relatively easy to track the gradual decline in the insecticidal activity of a treated net, in entomo-logical terms, using bioassays. We do not know how to translate this into measures of epidemiological protection. There is some evidence suggesting that epidemiological protection may extend beyond the period when the net is still giving “adequate” lev-els of activity as measured by bioassay, according to our rather arbitrary definition of “adequate”. This is a key question for planning systems for the re-treat-ment of nets and for the future use of “long-lasting” methods of net treatment.

3. THE ROLL BACK MALARIA ‘STRATEGIC FRAMEWORK’ FOR INSECTICIDE-TREATED NETS

The Roll Back Malaria “strategic framework” for ITNs in Africa grew from the realization that the Abuja targets2 for coverage with ITNs are unlike-ly to be achieved if we rely entirely on any one system, public, private or nongovernmental orga-nization. Commercial markets are valuable, and their expansion can probably be encouraged, but they are unlikely to be able to complete the task. They are especially unlikely to provide adequate coverage with insecticide-treated nets. On the other hand, the capacity of the public sector is also limit-

2 The Abuja target concerning bednets is to ensure that, by 2005, “at least 50% of those at risk of malaria, particularly children under five years of age and pregnant women, benefit from the most suitable combination of personal and community protective measures such as insecticide-treated mosquito nets and other interventions which are accessible and affordable to prevent infection and suffering” (The African summit on Roll Back Malaria, Abuja, Nigeria, April 25 2000 (WHO/CDS/RBM/2000.17; http://mosquito.who.int/docs/abuja_declaration.pdf)).


ed, and it has other responsibilities that are equal-ly or more important for public health, and that it currently fails to fulfil adequately. Simple financial constraints, and the many competing demands for urgent health funding, mean that we probably can-not afford to provide everyone in Africa with free ITNs, and we certainly cannot assume that we will be able to do so forever.

The strategic framework therefore proposes that subsidies should be focused on those who are most at risk, in order to ensure the maximum possible public health impact. It suggests that targeting preg-nant women is a good way to do this, partly because the net will also protect the new baby, and partly because antenatal care clinics offer a readily avail-able delivery mechanism, with generally high rates of attendance in Africa. However, we still have very little experience of this method of targeting, and more operational research is urgently needed.

The strategic framework also proposes that where possible, the subsidy should be delivered in the form of a voucher, which will allow the recipient to buy an ITN from a local shop at a heavily subsidized price. This is considered to be preferable to procur-ing the ITNs centrally and delivering them through the antenatal care clinic, which will tend to compete with, and may inhibit the growth of, local commer-cial markets in nets.

Vouchers, on the other hand, are expected to encour-age local traders to sell ITNs. Unfortunately, we have even less experience with vouchers than we do with targeting pregnant women. There are many unanswered operational questions here. Those that relate to the functioning of the system include: – How can we ensure that the voucher reaches the

intended recipient, and does not go astray in the clinic?

– How can we ensure that the recipient will use it to buy an ITN, and not other goods in the same shop?

– What proportion of ITNs bought in this way will be used by the pregnant woman, rather than by someone else?

– What system should be used for redemption, i.e. when a trader takes a voucher in return for a net, does he or she exchange it for cash at the local bank, or use it to obtain more nets from the wholesaler? What incentive margins will be needed to ensure the participation of local retail-ers, wholesalers, and others involved in the redemption system?

– In places where nets are currently rare, will a voucher scheme encourage local traders to begin selling them? In places where nets are already common, what will be the effect on prices?

– Should a voucher system also be used for insec-

ticide, and if so, what will be the effect on rates of treatment and re-treatment?

All these questions require careful operational research.

The strategic framework also suggests other ways in which commercial trade in ITN products could be encouraged. These include removal of tax and tar-iff barriers, and demand creation. In order to evalu-ate the effect of these market-related interventions, we need to monitor their impact on the structure and function of the markets, as well as the impact on coverage at the household level. Examples of ques-tions to be asked include:– When and how do tax and tariff reductions

translate into reduced prices?– How can we track the presence, price, and mar-

ket share of competing products at a national level?

– How can we track sales volumes where there are numerous small suppliers, or where most nets are sewn locally by tailors using a variety of material?

– In the United Republic of Tanzania, competition between factories and a rapid growth in sales volumes led to greatly improved quality and a substantial reduction in prices, but can this be expected to happen elsewhere?

– What is the effect of official attempts to regulate price and quality?

Many of these “supply side” questions can and should be complemented by information from the consumer side. For example, a great deal of useful information could be obtained from a household survey if the fieldworker could look at a net hang-ing on a bed, and could identify from this inspection when the net was bought, and the source of the net (e.g. by brand or manufacturer, project versus non-project, etc). This has not been attempted, but might not be too difficult, especially if suppliers could be persuaded to label their nets.

The strategic framework makes recommendations about what it calls “market priming”, i.e. the sale of a (usually subsidized) product through commer-cial channels. The aim of this is to encourage local demand, and at the same time to strengthen local distribution systems, so that the conditions are cre-ated in which an unsubsidized commercial market can take over. It is suggested that this kind of market priming is most appropriate in remote rural plac-es where there is currently little commercial activi-ty. The problem is that unsubsidized suppliers are unlikely to move in as long as the subsidized supply is there. How, then, can one judge that the market has been adequately primed, and that a commercial supply is willing and able to move in?


Mal

aria

Annex 7 WORKING PAPER: Improving and scaling up vector control, the impact of insecticide resistance and possible means of resistance management


IMPROVING AND SCALING UP VECTOR CONTROL, THE IMPACT OF INSECTICIDE RESISTANCE AND POSSIBLE MEANS OF RESISTANCE MANAGEMENT

C.F. CurtisLondon School of Hygiene & Tropical MedicineLondon, WC1E 7HT United Kingdom

This paper describes ways in which current meth-ods of vector control could be improved and scaled up, the impact of insecticide resistance and possi-ble methods by which such resistance could be man-aged.

1. RESIDUAL ADULTICIDES

In most circumstances, using residual insecticides in houses is the most efficient approach to the control of malaria transmission, because the chance of killing an anopheline mosquito is repeated every time the mosquito enters a house to bite, before the mosqui-to reaches the age at which it could contain mature sporozoites. The insecticide may be used in the form of an indoor residual spray (IRS) or for the treat-ment of a bednet. In either case, coverage of a high percentage of the houses in a community is required in order to achieve the full potential of the method to reduce the vectorial capacity of the local mosquito population (Magesa et al., 1991; Hawley et al., 2003). Historically the best results have been achieved by IRS, e.g. the reduction of the incidence of malaria in India from about 75 million cases per year in the 1930s to about 110 000 in the 1960s (a reduction of 99.8%) and the near eradication of previously holo-endemic malaria from Zanzibar, United Republic of Tanzania, in the 1960s. Results obtained so far with insectide-treated nets (ITNs) have not matched these achievements, but the use of ITNs requires less equipment and labour, and may be more feasible in many circumstances. Careful and unprejudiced con-sideration, backed up by more operational research (e.g. Curtis et al., 1998b; Kroeger et al., 2002), of the advantages and disadvantages of IRS and ITNs needs to be made in each individual case.

The recent impact of resistance of Anopheles funestus to pyrethroids but not to dichloro-diphenyl-trichlo-roethane (DDT), observed in the IRS programme in South Africa, is considered below.

2. INSECTICIDE-TREATED NETS

In situations in which insecticide-treated nets (ITNs) are chosen as the method of control, some consider that rural communities should be made to pay indi-vidually for them, with subsidies kept to a mini-mum so as not to discourage the development of the commercial sector (WHO, 2002). However, there are strong indications that ITNs can be more efficiently and comprehensively supplied by proactive teams visiting villages to supply nets and insecticide for every bed and other sleeping place in the village, free of charge. An annual visit needs to be made by one person to organize re-treatment of the nets and a further visit by the whole team after several years in order to replace badly torn nets. Experience in 28 villages in the United Republic of Tanzania has shown that this approach achieves much higher and more equitable coverage (including annual re-treat-ment of > 90% of nets) than marketing, and that the productivity of such proactive distribution teams is very high (Maxwell et al., 2003). Calculations made on the basis of this experience suggest that to sus-tain such a programme per million people would require about 35 full-time personnel, or the equiva-lent amount of work by more local part-time teams, at a total cost for materials, labour and transport of about US$ 1 million per million people per year. Operational research to check whether such high productivity can indeed be achieved with a scaled-up system should be undertaken urgently. In towns, nets are bought mainly as protection against nui-sance associated with Culex, and distribution there can safely be left to markets that are functioning quite well (Miller & Lines, 2002). Based on the above cost estimate for one million people, a donation sys-tem for all lowland tropical African villages would cost about US$ 0.3 billion per year – an eminent-ly affordable and sustainable expenditure, which is considerably less than that devoted to cat flea con-trol in the USA (Rust, 2002).

No one has ever proposed that vaccines should only be provided to children whose parents can be per-suaded to pay for them. Lessons can be learned on how child vaccination programmes, organized by the public sector with strong donor support and costing about US$ 1.1 billion per year in develop-ing countries, have proved to be sustainable under the most adverse circumstances There is an analo-gy between vaccination and ITNs in that there is a personal protection aspect in both cases, but the full potential of the method is only achieved if coverage is high, in order to achieve a community bonus (by reduction of the reservoir of pathogen in the case of vaccination, or by mass killing of mosquitoes attract-ed to occupied ITNs).


It has been suggested that ITNs supplied free of charge will be misused or sold, but in fact stud-ies so far indicate that almost all nets supplied on this basis reached and were used by their intend-ed recipients (Guyatt & Ochola, 2003); further such studies are needed.

In order to maximize mosquito mortality, the provi-sion of ITNs to both sexes and all age groups seems desirable, rather than targeting ITNs, to give only personal protection to pregnant women and young children who are the most vulnerable to malaria. However, this needs to be verified.

Fears have been expressed over several decades that, in areas of intense malaria transmission where acquired immunity is very important, reduction without eradication of malaria vectors could inter-fere with the build-up of immunity and postpone morbidity caused by malaria, without reducing the lifetime burden. Studies conducted 3–4 years after provision of ITNs (annually re-treated) showed that indeed the levels of antibodies to variant surface antigen were reduced, compared with the levels in people in a village without nets (Askjaer et al., 2001). However, fever and anaemia caused by malaria in young children were much reduced in the villag-es with ITNs (Maxwell et al., 2002) compared with unprotected villages. Older children showed little or no such benefit, but also showed no disadvantage, i.e. they were not “paying” for the benefit that they had received earlier by being more ill later in life. Such studies need to be extended over longer time periods and should include consideration of more severe consequences of malaria.

The evidence that ITNs function effectively despite the presence in the vector population of a high fre-quency of the kdr gene that confers resistance to pyrethoids is considered below.

3. LONG-LASTING NETS

It is thought that the need to re-treat nets may be removed by use of “long-lasting” nets, on which insecticidal activity is claimed to be wash-resis-tant. However, in comparisons of the commercial-ly available models with conventionally treated nets, a variety of results have been reported. These have ranged from loss of activity from both types of net after a very few washes (Killian, 2002; Müller, 2002), a definite advantage in wash resistance for the “long-lasting” product compared with conven-tional treatment (Gonzalez et al., 2002; Kayedi, in preparation) to long persistence of insecticidal effect on both types of net with little or no significant dif-ference between conventional treatment and “long-

lasting” products (Magesa et al., 2002; Graham et al., in preparation). The causes of this variability need to be clarified, especially in relation to the methods by which net owners actually wash their nets.

4. LARVAL CONTROL

Control of An. culicifacies larvae using larvivorous fish is reported to be working well in Karnataka state, India. However, it does not seem to be appli-cable to those anopheline mosquitoes which typical-ly breed in small puddles that frequently alternate between dryness and being re-filled with rainwa-ter, and in situations where there are many such sites within mosquito-flight range of a village. This applies to many An. gambiae rural breeding sites. In urban and suburban areas in Africa, a few promi-nent sites may be important contributors to the risk of malaria and concerted attempts to apply larvi-cides or biological control agents would seem to be worthwhile (Trape et al., 2001). This idea should be followed up with testing the cost–effectiveness of alternative larval control methods and intervention trials with adequate replication and controls. This was done in Sri Lanka with the insect growth reg-ulator pyriproxyfen in breeding sites in gem-min-ing pits where only two annual treatments were required to prevent adult emergence (Yapabandara et al., 2001, 2002). Success in this case, in achieving such high coverage that malaria was effectively con-trolled, was probably due to the fact that, although there were hundreds of such pits per village, their location was well known to the villagers. The pos-sibility of evolution of resistance to insect growth regulators has been thought to be very unlikely because these compounds are analogues of natu-ral hormones. However, resistance of the mosquito Ochlerotatus nigomaculis to the insect growth regu-lator methoprene has recently been reported after 20 years of using this product for control (Cornel et al., 2002). In future work using insect growth regu-lators against Anopheles, the possibility of resistance should be kept in mind.

5. INTRODUCING GENES FOR NON-SUSCEPTIBILITY TO INFECTION WITH PLASMODIUM INTO WILD ANOPHELES POPULATIONS

It is very likely that strains of Anopheles that are not susceptible (i.e. are refractory) to infection with Plasmodium falciparum will soon be genetically engi-neered (Ito et al., 2002). The question remains as to whether such constructs could be introduced into wild populations and whether this would have a sustainable impact on the natural transmission of malaria. There were would be no point in releas-


ing such a strain without a genetic driving system since a mass rearing facility would be required, and it would be more efficient to use this facility for the production of sterile males and with the aim of pop-ulation eradication.

Genetic driving systems have been considered which could cause a refractoriness construct to spread from a small seeding and to “resist” the effects of a limited amount of immigration. The systems main-ly considered are appropriate types of transpo-son (Kidwell & Ribeiro, 1992), Wolbachia infections (Curtis & Sinkins, 1999), and lethal-suppressor sys-tems leading to under-dominance for fitness (Davis et al., 2001).

It is quite possible that intensive work on any one of these driving systems would produce a system that could drive itself through a wild population. However, a problem raised by Curtis (1968) remains unsolved. This is the need for absolute linkage of a refractoriness construct to the chosen driving sys-tem. If recombinants occurred, even rarely, gener-ating individuals with the driving system without the “load” of the refractoriness construct, these indi-viduals would most probably have a fitness advan-tage over those carrying the loaded driving system. The consequence would be selection towards fixa-tion of the unloaded (and useless) driving system. Simulations suggest that recombination at rates as low as 10–6 with a fitness advantage for the unload-ed system of 20%, would prevent sustainable benefit from an attempt to drive a refractoriness construct into a population. It would not be possible to prove by laboratory experiments that such a low rate of recombination would not occur.

Boëte & Koella (2003) examined other evolutionary problems with this concept. It is recommended that, before devoting a large amount of effort to labora-tory production of refractory strains, the question should be seriously considered as to whether there is a real prospect that they can be used effectively in wild populations.

6. INSECTICIDE RESISTANCE

It is conventional in writing about malaria to list insecticide resistance of vectors as one of the impor-tant factors interfering with efforts to control the disease. Much work has been done on detection of resistance, using bioassays in which mosqui-toes are made to walk for one hour on paper treat-ed with standard doses of insecticide (WHO, 1986, 1992). The biochemical and molecular mechanisms of action of genes that confer resistance may broadly be classified as enhanced metabolism of insecticides

to non-toxic compounds, and changes in the sites of action in the insect nervous system so that these sites are no longer vulnerable to insecticidal action (Hemingway & Ranson, 2000). It has frequent-ly been pointed out that detection of the existence of such genes in a population does not necessari-ly mean that the insecticide will fail to give satisfac-tory control of the disease when applied in the field (Davidson & Zahar, 1973; WHO, 1986, 1992). If the study of resistance is to be more than an academic exercise, it is vital that convincing data are obtained on the operational implications of each example of resistance, so that rational decisions can be made about switching of insecticides. In reality, however, there are remarkably few cases in which such data are available. Some of the factors to consider are:1. Resistance genes generally only cause a rise in

tolerance level, not an absolute prevention of any killing by the insecticide; one must consid-er whether the conditions used for bioassays properly represent the exposure to insecticide received by free-flying wild mosquitoes.

2. Some resistance genes are only expressed in young adult mosquitoes and, after about age 10 days, susceptibility becomes more or less normal (Lines & Nassor, 1991; Rowland & Hemingway, 1987). Since completion of the spo-rogonic cycle takes more than 10 days, there is a good chance that a mosquito will encounter a spray deposit or treated net after its resistance has faded, but before reaching an age at which it could transmit malaria.

3. The irritant effect of DDT and pyrethroids could have an important influence either:(a) by driving mosquitoes out of houses and

into cattle sheds and thus reducing the risk of malaria transmission, even though few resistant mosquitoes are killed (Sharma et al., 1982, 1986; Roberts et al., 2000);

(b) because genes that confer resistance may not only reduce susceptibility to being killed by insecticide but may also reduce irritability (Hodjati & Curtis, 1997), so that resistant mosquitoes rest longer on insec-ticide deposits and eventually pick up a lethal dose of insecticide (Rowland, 1990; Darriet et al., 2000).

4. In making historical comparisons of the effect of an insecticide before and after resistance arose, or before and after switching insecticides, it is essential that the possible effects of differenc-es in the percentage of treated houses or nets are taken into account.

5. If an increase in frequency of a resistance gene is detected over time in an insecticide-treated area, this indicates that, under at least some circum-stances, insects with the gene for resistance are


able to survive whereas those with the allele for susceptibility are dying. However this does not necessarily prove that the resistance is interfer-ing with vector control because, in several cases (e.g. Georghiou, 1990), there is evidence that it is residues of agricultural insecticides, rather than insecticides applied for vector control, which select for resistance in vector populations.

The following sections will review some instances in which there is strong evidence that resistance genes in vector populations have interfered with malaria vector control, and other cases where they have not.

6.1 Evidence that resistance to DDT has operational impact

It is widely believed that the failure to eradicate malaria in the 1960s was solely due to the emer-gence of resistance to DDT in vector populations. In fact, other economic and administrative factors played an important role in this failure (Sharma & Malhotra, 1986). Furthermore, there is evidence that house spraying with DDT against vector popula-tions with high frequencies of resistance genes has some impact on malaria transmission and is better than abandoning all affordable attempts at vector control (Sharma et al., 1982, 1986). This impact pre-sumably arises because DDT is an irritant in mos-quitoes and tends to drive zoophilic species, such as An. culicifacies, from sprayed human dwellings towards cattle sheds. Indeed Roberts et al. (2000) consider that the main mechanism by which DDT has reduced malaria transmission (even where the vectors are susceptible) is by diversion away from dwellings, rather than by killing. Nevertheless, in India, the Islamic Republic of Iran and Zanzibar (United Republic of Tanzania), results of spraying with DDT in more recent times, when resistance genes are detectable in vector populations, have not been so good as in the 1960s when most vector pop-ulations scored as susceptible in bioassays.

In India, the recorded incidence of cases of malar-ia in the 1960s had been reduced by about 99.8% compared with estimates from before introduc-tion of spraying with DDT (about 110 000 cases per year compared with 75 million). More recent-ly, among extensive data available on the occurrence of genes conferring resistance in An. culicifacies and An. stephensi populations, there are many instanc-es of disappointingly limited reductions of the inci-dence of malaria after spraying with DDT. In many of these instances it is difficult to ascertain wheth-er the percentage of houses sprayed in recent times was comparable to that in the era of enthusiastic campaigning for the national eradication of malar-

ia. However, some data on spraying coverage and incidence of malaria before and after a switch from DDT to another insecticide have been published. For example, Doke et al. (2000) reported from the state of Maharashtra, where An. culicifacies is known to show strong resistance to DDT in bioassays, that a switch from DDT to lambda-cyhalothrin was associated with a decline in the number of cases of malaria caused by P. falciparum from 47 to 11. In the year before the switch, room coverage with DDT was reported as 81%. After the switch, household-ers were more enthusiastic about spraying because pest insects were more obviously being killed, and coverage rose to 92%, but it seems unlikely that this increase would be enough to explain the better con-trol of P. falciparum. It seems that at least part of the explanation was better performance of the newer insecticide, which does not show cross-resistance to the metabolic form of resistance to DDT present in India.

In Baluchestan, the Islamic Republic of Iran, Manoucheri et al. (1975) recorded that An. culici-facies was fully susceptible in bioassays with DDT in 1959 and almost disappeared in association with spraying with DDT and malathion from 1967 to 1973. However, in 1973 the vectors reappeared and showed strong resistance in bioassays, and a serious increase in the incidence of malaria was recorded. This occurred despite the fact that far more of the vectors were found in unsprayed than in sprayed houses, i.e. diversion away from sprayed houses was still occurring despite the build-up of resistance in the population.

In Zanzibar, malaria was reduced from holoendem-ic levels to near eradication between 1958 and 1968 by spraying with DDT, coupled with treatment of malaria patients with chloroquine. The level of con-trol was far higher than has been achieved with any of the recent trials of insecticide-treated nets. The programme in Zanzibar was suddenly terminated in 1968 and at that time there were no reports of resistance in the vectors. Unpublished reports by G. Davidson at about that time referred only to An. ara-biensis as a malaria vector in Zanzibar. More than 10 years after spraying was terminated, DDT-resistant An. gambiae s. s. were described from Zanzibar in unpublished reports by V. Ariaratnam and by Curtis et al., cited by Lines & Nassor (1991). The frequen-cy of resistance was much higher in An. gambiae s. s. than An. arabiensis (J. Lines, unpublished). The mechanism of the resistance, which does not give cross-resistance to pyrethroids, has been established by Prapanthadara et al. (1995). It would appear that as the residues of DDT decayed the more endophilic species, An.gambiae s. s., was able to recover. It may


have been selected for the resistance gene after 1968 because the decayed DDT residues allowed survival of heterozygotes for the gene conferring resistance, which had probably been unable to survive when spray deposits in houses were regularly renewed. An alternative possibility is that a high frequency of DDT resistance already existed in An.gambiae s. s. before 1968, but the resistance genes were not suf-ficiently protective to allow this species to recover to a detectable density until the pressure of regu-lar spraying was relaxed. In the 1980s, there was a revival of spraying with DDT in Zanzibar, but it had almost no impact on malaria. House coverage was probably not as good as in the eradication campaign in the 1960s, but it would seem that the resistance was one of the causes of the very disappointing results.

6.2 Resistance to malathion in An. stephensi in the Islamic Republic of Iran and Pakistan

After switching from DDT to malathion for spray-ing in the Islamic Republic of Iran and in Pakistan in the 1970s, resistance to malathion developed (Manoucheri et al., 1976; Rathor & Toqir, 1980). Nevertheless, use of malathion continued to reduce incidence of falciparum and vivax malaria, although not as well as did lambda-cyhalothrin (Rowland et al., 1994, 1997). It was suggested that the fading of resistance to malathion with age, mentioned above, may have allowed this insecticide to kill many of the mosquitoes carrying genes conferring resistance before they reached an age at which they could be infective.

6.3 Evidence that resistance to pyrethroids in An. funestus in South Africa had an operational impact

Spraying of houses with DDT was used in South Africa from 1945 to 1995, with a successful impact on malaria; no detection of resistance to DDT was observed in either of the two vector species and An. funestus was apparently eradicated. A switch was made in 1996 to spraying with a pyrethroid in KwaZulu Natal. Within 4 years, notified cases of malaria had increased about four-fold, An. funes-tus had reappeared and was observable emerging alive from pyrethroid-sprayed houses, and bioas-says showed that this species was resistant to pyre-throids but not to DDT (Hargreaves et al., 2000). A decision was taken to switch back to DDT spray-ing and, in the 2 years since this was put into effect, An. funestus is no longer observed emerging alive from sprayed houses (Brooke et al., 2001) and noti-fied cases of malaria have declined by 91% (Sharp, 2002). There has also been a switch in the first-line

antimalarial drug that is used, but it seems clear that the emergence of resistance to pyrethroids, and the avoidance of its effects by switching to DDT, have been of major operational importance. For An. funes-tus from nearby southern Mozambique, there is evidence for a metabolic form of resistance to pyre-throids that confers cross-resistance to carbamates (Brooke et al., 2001).

6.4 Evidence that kdr genes in An. gambiae s. s. in Côte d’Ivoire and Kenya do not prevent effective use of pyrethroid-treated bednets

There is now major emphasis on ITNs as the most feasible means of reducing malaria transmission. The fact that only pyrethroids have so far been oper-ationally used for the treatment of nets and that resistance to one pyrethroid leads to cross-resistance (at varying intensity) to this whole class of insec-ticides had led to pessimistic views (e.g. Curtis et al., 1998a) about the likelihood that pyrethroid resis-tance would soon block further effective use of treat-ed nets. However, in Sichuan, China, where millions of nets were treated annually, the anopheline vec-tor remained susceptible to pyrethroids (Kang et al., 1995). Furthermore, where kdr genes (knock-down resistance to pyrethroid, caused by alteration in voltage-gated sodium channels in the insect ner-vous system) and/or genes conferring resistance to pyrethroids on the basis of metabolic mechanisms, exist in An. gambiae s. s. in Côte d’Ivoire (Chandre et al., 1999a, 1999b) and Kenya (Vulule et al., 1994; Ranson et al., 2000), they apparently do not prevent effective use of treated nets.

In Côte d’Ivoire, it is thought that the kdr gene was selected in An. gambiae s. s. owing to earlier use of DDT for malaria control, or domestic or agricultur-al use of pyrethroids (Chandre et al., 1999b). Near Bouaké, where the frequency of kdr is high, there have been repeated trials of pyrethroid-treated nets in experimental huts into which wild An. gambiae s. s. can enter and attempt to bite sleepers. Reductions of blood feeding with treated nets with holes cut in them can be considered as evaluation of the person-al protection that the pyrethroid deposit on the net would give to the sleeper under the net. Mosquito mortality is an indication that such nets used in a whole community would have an impact (a “mass effect”) on the population of infective vectors. Both types of impact have been recorded with nets treat-ed with various pyrethroids, in comparison with untreated nets (Darriet et al., 1998, 2000; Chandre et al., 1999a, 1999b; Guillet et al., 2001; N’Guessan et al., 2001; Asidi et al., 2004). The comparative data of Darriet et al. (2000), at a site where the frequen-cy of kdr was much lower than that near Bouaké,


showed impacts that were no greater than at the site where the frequency of kdr was high. It is suggested that this apparently paradoxical result is because the kdr gene causes reduced irritability to pyrethroids, which is reflected in the reduced tendency for the population in which the frequency of kdr is high to exit from huts with pyrethroid-treated nets (Darriet et al., 2000). Thus, they remain in contact with the pyrethroid deposit for a longer time and eventual-ly pick up a dose that is high enough to kill them, despite their resistance. Kolaczinski et al. (2000) reported poor results with nets treated with alpha-cypermethrin or etofenprox in the site where the fre-quency of kdr was high. However, Asidi et al. (2004) obtained quite good results with alpha-cyperme-thrin.

Tests have also been carried out on a village scale with nets treated with pyrethroids in areas with a high frequency of kdr. An initial trial in the sin-gle small village of Kafine was not conclusive, although there were indications of an impact on the rate of parity (a measure of mosquito survival) of An. gambiae (Doannio et al., 1999) and on preva-lence of high parasitaemia and incidence of malar-ia attacks in children (Henry et al., 1999). Trials have been extended to multiple villages in the Korhogo area of Côte d’Ivoire where the frequency of kdr is 94%. The results have been reported at several con-ferences (e.g. Dossou-Yovo et al., 2000; Carnevale, 2001), but unfortunately not yet comprehensively in a journal. There are clear indications from the data that, despite the high frequency of the kdr gene, the pyrethroid-treated nets had a significant impact on the population density of the vector and on the spo-rozoite rate (and hence on the entomological inoc-ulation rate), and on parasite load and morbidity caused by malaria in children. The effects on malar-ia in children might be explained by the physical barrier provided by the nets, even if the insecticide was ineffective against the mosquitoes carrying the kdr gene, but the “mass effects” on the vector popu-lation can only be explained by a sustained insecti-cidal effect against these mosquitoes.

On the shores of Lake Victoria in Kenya, Vulule et al. (1994, 1999) reported an increase in pyrethroid tolerance in An. gambiae s. s. associated with use of treated nets or curtains and with elevated levels of oxidases and esterases in the mosquito. Ranson et al. (2000) reported finding a kdr gene that differed by one nucleotide from that found in West Africa. Deliberate tests of whether these resistances have an impact on the effectiveness of treated nets have not yet been reported. However, not far from where these resistant mosquitoes were collected, a major trial of treated nets has been carried out (Hawley

et al., 2003; Phillips Howard et al., 2003). This trial showed the largest impact yet recorded, attributable to treated nets, on childhood mortality, and the most extensive data on the community-wide (“mass”) effect of treated nets on vector populations. Thus it appears that the presence in vector populations of two forms of resistance to pyrethroids is not incon-sistent with excellent impact of treated nets.

It would be very unwise to be complacent about this possible threat to the main available meth-od of malaria prevention in low-income countries. Stronger forms of resistance, e.g. super-kdr as found by Sawicki et al. (1978) in house flies, might arise in malaria vectors. However, the pessimism felt a few years ago, when genes conferring resistance to pyre-throids were first reported in An. gambiae, has now been somewhat alleviated.

6.5 Resistance to carbamate and pyrethroids in nuisance insects affected by treated nets

Users of treated nets notice their impact on nui-sance biting insects, such as Culex quinquefasciatus mosquitoes and Cimex hemipterus bedbugs, and it is probable that, in areas where high rates of use and re-treatment have been sustained, this is at least as much because of the impact of the nets on nuisance insects as on malaria vectors. Thus the impact of genes conferring resistance in these insects is a valid topic to consider in relation to malaria control.

At Muheza, United Republic of Tanzania, where numerous trials have been conducted on various treatments on nets in experimental huts, very low mortality of Cx quinquefasciatus has been observed consistently, in contrast to high mortality of pyre-throid-susceptible An. gambiae s. s. and protection from biting by both these mosquito species (Curtis et al., 1996). Cx quinquefasciatus at that site score as resis-tant to pyrethroids in laboratory tests (Khayrandish & Wood, 1993). It is not known whether this resis-tance is the cause of the low mortality observed in the huts, or whether the low mortality is attributable to irritability, causing reduced contact of these mos-quitoes with the nets.

In Côte d’Ivoire, Cx quinquefasciatus carries genes conferring resistance to both pyrethroids and car-bamates (Chandre et al., 1997). The latter is due to alteration in the target site of the insecticide on ace-tyl cholinesterease. However, in experimental huts, considerable mortality has been observed with nets treated with pyrethroids, and mortality of 80–95% when they are treated with the carbamate carbosul-fan (Kolaczinski et al., 2000; Asidi et al., 2004). These are the highest mortality rates ever recorded with


treated nets in experimental huts and indicate that the presence of altered acetyl cholinesterease does not prevent nets treated with carbosulfan being highly effective.

When pyrethroid-treated nets have been intro-duced, it has frequently been observed that bed-bug infestations are eliminated (e.g. Njunwa et al., 1991; Temu et al., 1999). In five villages near Muheza in Tanzania, after 6 years using treated nets, com-plaints that bedbugs had returned were received. Bioassays showed that in these five villages the bedbugs were highly significantly more tolerant of pyrethroids than the bedbugs in five villages with-out treated nets (Myamba et al., 2002). It is clear that this tolerance (the mechanism for which has not yet been ascertained) is allowing a serious resurgence of a nuisance problem that could threaten continued enthusiasm for treated nets.

7. MANAGEMENT OF RESISTANCE

In discussing the management of resistance, it is conventional to mention use of non-insecticidal con-trol and limitation of the application of insecticide to areas and seasons where and when it is really need-ed. If these can be done feasibly and cost-effectively, a well-organized vector control programme would do them in any case, quite apart from their assis-tance in reducing selection pressure for resistance.

The possible dangers of not maintaining high enough doses of insecticide to kill insects that are heterozygous for the gene conferring resistance has been mentioned in section 6.1 as a possible cause of initiation of a resistance problem. Low doses of antimalarial drugs as a cause of selection for drug resistance are often mentioned, but for a haploid such as Plasmodium it is not obvious how low doses could be a danger; the case is clearer with diploid insects. In diploids, in the early stages of the evo-lution of resistance, the genes concerned would be almost all present in heterozygotes and resistance may be an incompletely recessive trait. The hetero-zygotes would thus be killed, along with the suscep-tible homozygotes, at normal operational doses. The gene conferring resistance may only gain a selective advantage when the insecticide deposit decays and is not renewed on schedule. Thus timely re-spray-ing may be considered as a form of management of resistance.

Any reasonably well-organized vector control pro-gramme should be prepared to switch insecticide to an affordable and safe alternative that does not show cross-resistance to an emergent form of resis-tance, if there is good reason to believe that resis-

tance is interfering with effective vector control. It is to be hoped that, if the switch is made before the resistance has reached a very high frequency, nat-ural selection will act against the genes conferring resistance and eventually allow re-use of the orig-inal insecticide, before resistance to the alternative compound(s) also becomes a problem.

It has frequently been suggested that, to pre-empt resistance ever reaching a frequency at which it could cause interference with vector control, one should rotate the use of different insecticides over time, or apply them in a “mosaic”, e.g. using different insec-ticides in neighbouring houses. These concepts have been tested with house spraying against An. albima-nus in Mexico (Hemingway et al., 1997; Rodriguez Ramirez, 2000). One would expect that a rotation or mosaic would lessen the overall selection pressure for resistance to one of the compounds, compared with exclusive use of that compound. Preliminary indications from the Mexican trial seemed to agree with this expectation (Rodriguez Ramirez, 2000). The difference in level of resistance to pyrethroids between the singly-sprayed area and the rotation and mosaic areas has more recently been confirmed to have reached statistical significance (Hemingway, 2002). By bringing into use an organophosphate or a carbamate in a rotation or mosaic, one is expos-ing the population to selection pressure for resis-tance to these compounds from the outset, whereas such selection would be postponed if a switch were not made until a serious level of resistance to the pyrethroid had been detected. So far in the Mexican trial there has not been a serious build-up of the low levels of resistance to organophosphate and car-bamate (Rodriguez Ramirez, 2000), but one might expect this to occur eventually. Computer simula-tions, based on a simple genetic model, suggest that there would be no long-term difference in the time before a high level of double or triple resistance was reached with a pre-planned rotation or mosaic sys-tem, compared with a system of switching when tests for resistance show it to be necessary (Curtis et al., 1993). However, by introducing assumptions about genes that modify fitness one can make a case for a pre-planned rotation or mosaic being a superi-or strategy. It would be laborious, but is important, to clarify whether this is true.

The idea of using of mixtures of insecticides, for which there is absolutely no cross-resistance, to delay the build-up of resistance is based on an entirely different principle to that of rotating or switching insecticides. If a mixture were introduced when resistance to both components is rare, double resistant insects would be extremely rare and would be greatly outnumbered by insects that escape all


contact with insecticide. Among the insects that did encounter the mixture, the relatively common indi-viduals that were singly resistant to component A of the mixture would be killed by B, and vice versa. Theoretically, under the right circumstances, this could be a highly effective way of enjoying the ben-efits of use of insecticide without risking build-up of resistance (Curtis et al., 1993). The circumstanc-es required for successful use of this principle are rather demanding. One of the requirements is an adequate dose of each component, which would be expected to approximately double the expenditure required on insecticides, compared with normal use of a single insecticide. This might be avoided if there is synergism between the components of the mix-ture, so that a relatively low dose of each compo-nent in the mixture would give reliable mortality of exposed individuals carrying either of the genotypes conferring susceptibility. There have been reports of synergism between a carbamate and a pyrethroid in An. gambiae s. s. (Corbel et al., 2002). However, the synergism was only found in a certain dose range. Furthermore, cross-resistance to carbamate/pyre-throid, as reported by Brooke et al. (2001) and Asidi et al. (2001), would prevent effective use of a mix-ture of these classes of insecticide to delay build-up of resistance. However, the concept of synergism is well worth keeping in mind and investigating.

8. RECOMMENDATIONS

1. In view of the high productivity and coverage achieved by teams distributing and re-treating ITNs proactively and free of charge, the feasi-bility of scaling up distribution on this basis, in comparison with marketing systems, should be further investigated.

2. Further work on genetically engineered mos-quitoes that are refractory to infection with Plasmodium should only be encouraged if there appears to be a practical means of retaining the necessary complete genetic linkage between the refractoriness construct and a system for driving it into a wild population.

3. The evidence base on the cost–effectiveness of larval and integrated control in various ecologi-cal circumstances should be expanded.

4. Much more attention should be given than hith-erto to the question of to what extent detected examples of insecticide resistance interfere with practical use of insecticides for vector control.

5. To help reaction to, or prevention of evolution of resistance to insecticides, the database on fea-sible alternative insecticides that do not show cross-resistance should be expanded.

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Mal

aria

Annex 8 WORKING PAPER: Strategies for scaling up intermittent preventive treatment for malaria and anaemia in pregnant women and in children


STRATEGIES FOR SCALING UP INTERMITTENT PREVENTIVE TREATMENT FOR MALARIA AND ANAEMIA IN PREGNANT WOMEN AND IN CHILDREN

Clara MenendezCenter for International HealthHospital Clinic/University of BarcelonaBarcelona, SpainandManhiça Health Research Center (CISM)Mozambique

1. BACKGROUND

The greatest burden of mortality and morbidity caused by malaria falls on pregnant women and children living in areas of stable malaria transmis-sion, which are mainly concentrated in sub-Saharan Africa. This has enormous, although difficult to quantify, social and economic implications.

Reduction of this burden depends on a combina-tion of adequate management of clinical malaria attacks with safe, efficacious and affordable drugs (and other means and materials), and effective pre-vention of infection.

At present, and despite many years of research on malaria, there is a paucity of available tools for the prevention of malaria, these being basically limit-ed to insecticide-treated nets and prophylaxis with antimalarial drugs (chemoprophylaxis). Although the idea of a vaccine against malaria is becoming more real, it is likely to be many years before an effective vaccine is available for large-scale imple-mentation through the Expanded Programme on Immunization (EPI).

The current WHO/Roll Back Malaria recommenda-tions for the control of malaria are:– Intermittent preventive treatment (IPT) with

sulphadoxine/pyrimethamine (SP) for pregnant women;

– Insecticide-treated nets and other materials;– Prompt presumptive treatment of clinical

attacks with an effective drug.

2. INTERMITTENT PREVENTIVE TREATMENT DURING PREGNANCY

Epidemiological studies consistently report an increased risk of malaria during pregnan-

cy (McGregor, 1984; Brabin, 1991; Nosten, 1991; Menendez, 1995). The clinical manifestations, sever-ity and frequency of the infection depend markedly on the level of immunity to malaria, which in gen-eral reflects the level of exposure to the infection and therefore the intensity of malaria transmission in the area. While malaria may be a common cause of maternal and perinatal mortality in areas of low and unstable endemicity, it is rarely a direct cause of death in settings of stable transmission, although it may indirectly contribute to mortality through the development of anaemia in the mother and low birth weight in the fetus. In the latter situation, it is difficult to estimate the overall impact of malar-ia infection on maternal and infant mortality, which still remains to be accurately established.

It is important to bear in mind that maternal deaths that are directly attributable to malaria are not an uncommon finding in areas of stable transmission coexisting with “pockets” of low or no transmis-sion, such as it is the case in some big African cities (Granja et al., 1998).

Depending on endemicity, the risk and severity of malarial disease is increased in women with lower parities, and a tendency for parasites to accumu-late in the placenta in these women. This pattern may be changing due to the AIDS epidemic and its interaction with malarial immunity, which is reflect-ed in increased severity of the disease, as well as in similarity of risk across among women with dif-ferent parities in areas where transmission is stable (Steketee et al., 1996, Verhoeff et al., 1999).

The enormous potential health consequences that malarial infection entails for the pregnant woman and her baby mean that protection against infection during pregnancy is a health priority. Malaria con-trol activities should take into account epidemio-logical variations in the pattern of malaria, as well as the level of the AIDS epidemic. Prevalence of P. vivax in the area is another factor to consider when deciding the strategy for control of malaria during pregnancy (Nosten et al., 1999).

In controlled trials, weekly and fortnightly che-moprophylaxis during pregnancy with efficacious antimalarials has been shown to reduce maternal anaemia and the proportion of low-birth-weight babies (Gulmezoglu & Garner, 1998). However, fail-ure in the provision of antimalarials by the health service, together with poor compliance, have limit-ed the effectiveness of this strategy.

To overcome this situation, a promising preventive approach using antimalarial drugs, ideally admin-


istered as a single-dose regimen at specified inter-vals during pregnancy, was proposed. The efficacy of intermittent preventive treatment (IPT) with SP in preventing malaria during pregnancy was eval-uated in four published studies, all carried out in east Africa (Schultz et al., 1994; Parise et al., 1998; Verhoeff et al., 1998; Shulman et al., 1999). Only one of these studies used a randomized, double-blind placebo-controlled design. In this study, a signifi-cant reduction in maternal anaemia was found at week 36, but the study lacked the statistical power to assess the effect on birth weight (Shulman et al., 1999). Different levels of efficacy on different out-comes were observed between the four studies. There are recent reports indicating that two doses of SP are not sufficiently protective enough for the prevention of malaria in HIV-infected pregnant women, calling for studies to determine optimal doses and dosing schedules for this special group. While it is possible that high doses may protect HIV-infected women against malaria, there are worries that increased doses of SP may exacerbate adverse skin reactions in this group of women. Adherence of pregnant women to recommended doses of IPT is another question that may greatly influence the level of effectiveness of this strategy. Compliance with two doses has been reported to be low in Malawi, the country with greatest experience (more than 8 years) in the implementation of IPT (Rogerson et al., 2001). Understanding the reasons (sociocultural, programmatic etc.) for this poor compliance is crit-ical for the improvement of the effectiveness of this intervention.

Despite this incomplete evaluation (in terms of safety, efficacy against different end-points and in different areas where malaria is endemic, and acceptability) this strategy is currently recommended by WHO for the control of malaria during pregnancy in areas of stable transmission, and it is part of the national malaria control programme in Kenya, Malawi and the United Republic of Tanzania. Clearly, a more rig-orous and systematic evaluation of this strategy is required in order to understand its full potential.

3. INTERMITTENT PREVENTIVE TREATMENT IN INFANTS

There is an increasing body of evidence from both clinical and epidemiological studies that severe anaemia acquired as a consequence of falciparum malaria shows a marked age-dependency, being particularly common in infants and young children (Slutsker et al., 1994; Marsh et al., 1995; Schellenberg et al., 1999). As intensity of transmission increas-es, the age pattern of disease is shifted to the left, and a considerable proportion of severe disease

and mortality consequently concentrates in young children and infants. Even in areas of lower trans-mission, the absolute number of deaths caused by malaria in infants may be disproportionately high (Schellenberg et al., 2004). Overall, severe anaemia as a result of malaria is likely to be the most impor-tant cause of death attributable to falciparum infec-tion in areas in which malaria is endemic in Africa. Severe anaemia, due to its insidious and unspecif-ic symptomatology, is likely to be massively under-recognized (Menendez, Fleming & Alonso, 2000).

As for pregnant women, there is a need for malaria control strategies to take into consideration the geo-graphical variations in the pattern of malaria in chil-dren.

The control of malaria using insecticide-treated nets has been shown to reduce morbidity and mortali-ty in several controlled studies across sub-Saharan Africa (Alonso et al., 1991; Lengeler, 2000) and it is currently recommended by WHO to prevent malar-ia in children. Mortality and severe morbidity can also be reduced by chemoprophylaxis, given at weekly or fortnightly intervals (Greenwood et al., 1988, 1995; Menon, 1990). However, this is difficult to sustain and may both accelerate the spread of drug resistance and impair the development of nat-ural immunity to malaria.

Intermittent prophylaxis may optimize the use of antimalarials for the prevention of malaria in children by retaining some of the benefits of and reducing the problems associated with regular che-moprophylaxis. The first published study on IPT in infants (IPTi) was conducted in the United Republic of Tanzania (Schellenberg et al., 2001). Through this randomized, double-blind placebo-controlled trial, a single dose of SP was administered at the time of routine immunizations at age 2, 3 and 9 months in the health-care facilities. The study results showed a reduction in the incidence of clinical malaria and anaemia, without impairment of acquired immunity or interference with the serological responses to the routine vaccines. Within the limitations of its small sample size, the study did not reveal any adverse reactions to SP.

After the publication of the results of the Ifakara study in the United Republic of Tanzania and rec-ognizing the need to fully explore the potential of an intervention within a rigorous and comprehen-sive approach, an international consortium was established by a number of international institutions with the aim of evaluating all the issues that are of relevance when considering its wide-scale imple-mentation. This includes efficacy in different epide-


miological settings, effectiveness, safety, interactions with new routine vaccines, impact on drug resis-tance and acceptability.

4. MOVING FROM EFFICACY STUDIES TO WIDE-SCALE IMPLEMENTATION

Assuming that IPT for both pregnant women and young children has been fully evaluated and found to be the best malaria control strategy for the coun-try, its implementation in programmes within a particular country would be accelerated by the fol-lowing steps: 1. International commitment and provision of

facilities and resources;2. Encouragement and support from the ministries

of health of effective partnership between the malaria control programme and the communi-ty preventive department, with clearly defined roles in the process of implementation at all lev-els: national, district and local;

3. Inform and educate national policy- and key decision-makers (including obstetricians and paediatricians) about the burden of malaria in pregnant women and children and the effective-ness and cost–benefits of this preventive strate-gy;

4. Use of the existing health infrastructure: the antenatal clinic for IPT in pregnancy and the EPI clinic for IPTi;

5. Integration with other preventive health activ-ities: the times of scheduled visits for antena-tal care or the times of routine vaccinations or weighing clinics for nutritional control;

6. Incorporation and training of existing health personnel of preventive services;

7. Understanding the sociocultural determinants of the use of preventive services (antenatal clin-ics and EPI programme) and of compliance with taking of drugs by healthy populations;

8. Continuous community information and health education about the burden and consequenc-es of malaria infection during pregnancy and in children, and the importance and benefits of prevention.

References

Alonso PL et al. (1991). The effect of insecticide-treat-ed bed nets on mortality of Gambian children. The Lancet, 337:1499–1502.

Brabin BJ (1991). The risks and severity of malaria in pregnant women: including a summary of current field research with identification of research priorities related to appropriate methods of prevention of malaria in pregnancy. Geneva, World Health Organization (TDR FIELMAL 1; Applied Field Research in Malaria Reports, No. 1; http://whqlibdoc.who.int/hq/1991/TDR_FIELDMAL_1.pdf, accessed 27 April 2004)

Greenwood BM et al. (1988). Comparison of two strat-egies for control of malaria within a primary health care programme in The Gambia. The Lancet, 1:1121–1127.

Greenwood BM et al. (1995). Mortality and morbidity from malaria after stopping malaria chemoprophylax-is. Transactions of the Royal Society for Tropical Medicine and Hygiene, 89:629–633.

Granja AC et al. (1998). Malaria-related maternal mortality in urban Mozambique. Annals of Tropical Medicine and Parasitology, 92:257–263.

Gulmezoglu AM & Garner, P (1998). Malaria in pregnancy in endemic areas. In: Garner P et al., eds. Infectious diseases module. Cochrane Database of Systematic Reviews [updated 4 March 1997]. The Cochrane Library, Cochrane Collaboration Issue 2, Oxford: Update Software.

Lengeler C (2000). Insecticide-treated bednets and curtains for preventing malaria. Cochrane Database of Systematic Reviews, (2):CD000363.

McGregor IA (1984). Epidemiology, malaria and pregnancy. American Journal of Tropical Medicine and Hygiene, 33:518.

Menendez C (1995). Malaria during pregnancy: a pri-ority area of malaria research and control. Parasitology Today, 5:178–181.

Menendez C, Fleming A, Alonso PL (2000). Malaria-related anaemia. Parasitology Today, 16(11):469–475.

Menon A et al. (1990). Sustained protection against mortality and morbidity from malaria in rural Gambian children by chemoprophylaxis given by vil-lage health workers. Transactions of the Royal Society for Tropical Medicine and Hygiene, 84:768–772.

Nosten F et al. (1991). Malaria in pregnancy in an area of unstable endemicity. Transactions of the Royal Society for Tropical Medicine and Hygiene, 85:595–603.

Nosten F et al. (1999). Effects of Plasmodium vivax in pregnancy. The Lancet, 354:546–549.


Parise ME et al. (1998). Efficacy of sulfadoxine-pyrimethamine for prevention of placental malar-ia in an area of Kenya with a high prevalence of malaria and human immunodeficiency virus infec-tion. American Journal of Tropical Medicine and Hygiene, 59:813–822.

Rogerson SJ et al. (2001). Intermittent sulphadoxine-pyrimethamine in pregnancy: effectiveness against malaria morbidity in Blantyre, Malawi, 1997–1999. Transactions of the Royal Society for Tropical Medicine and Hygiene, 94:549–553.

Schellenberg D et al. (1999). African children with malaria in an area of intense Plasmodium falciparum transmission: features on admission to hospital and risk factors for death. American Journal of Tropical Medicine and Hygiene, 61:431–438.

Schellenberg D et al. (2001). Intermittent treatment for malaria and anaemia control at time of routine vacci-nations in Tanzanian infants: a randomised, placebo-controlled trial. The Lancet, 357:1471–1477.

Schellenberg D et al. (2004). Changing epidemiolo-gy of malaria in Ifakara Town, southern Tanzania. Tropical Medicine & International Health, 9:68–76.

Shulman CE et al. (1999). Intermittent sulphadoxine-pyrimethamine to prevent severe anaemia secondary to malaria in pregnancy: a randomized placebo-con-trolled trial. The Lancet, 353:632–636.

Schultz LJ et al. (1994). The efficacy of anti malar-ia regimens containing sulfadoxine-pyrimethamine and/or CQ in preventing peripheral and placen-tal Plasmodium falciparum infection among preg-nant women in Malawi. American Journal of Tropical Medicine and Hygiene, 51:515–522.

Slutsker L et al. (1994). In-hospital morbidity and mortality due to malaria-associated severe anaemia in two areas of Malawi with different patterns of malar-ia infection. Transactions of the Royal Society for Tropical Medicine and Hygiene, 88:548–551.

Marsh K et al. (1995). Indicators of life-threatening malaria in African children. New England Journal of Medicine, 332:1399–1404.

Steketee RW et al. (1996). Impairment of a pregnant woman’s acquired ability to limit Plasmodium falci-parum by infection with human immunodeficiency virus type-1. American Journal of Tropical Medicine and Hygiene, 55(Suppl.):42–49.

Verhoeff FH et al. (1998). An evaluation of the effects of intermittent sulfadoxine-pyrimethamine treat-ment in pregnancy on parasite clearance and risk of low birth weight in rural Malawi. Annals of Tropical Medicine and Parasitology, 92:141–150.

Verhoeff FH et al. (1999). Increased prevalence of malaria in HIV-infected pregnant women and its implications for malaria control. Tropical Medicine and International Health, 4:5–12.


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Annex 9 WORKING PAPER: Novel molecular methods for surveillance of resistance to antimalarial drugs in the field


NOVEL MOLECULAR METHODS FOR SURVEILLANCE OF RESISTANCE TO ANTIMALARIAL DRUGS IN THE FIELD

Abdoulaye A. Djimdé and Ogobara K. DoumboUniversity of BamakoMali

1. INTRODUCTION

Since no vaccine is available and vector control mea-sures have proven very difficult to sustain in most endemic settings, the control of malaria relies pri-marily on chemotherapy. Chloroquine is the ideal drug for treating uncomplicated malaria, because it is cheap and well tolerated at therapeutic doses. However, resistance to chloroquine appeared in the late 1950s and 1960s, probably arising in four distinct foci in South America, south-east Asia and Papua New Guinea, and has subsequently spread to almost all areas in which malaria is endemic, includ-ing sub-Saharan Africa (Wellems & Plowe, 2001). In several eastern and southern African countries, chloroquine has now failed and has been replaced by sulfadoxine/pyrimethamine as the first-line anti-malarial drug (Barat et al., 1998).

In order to cope with the spread of drug resis-tance, governments in countries in which malaria is endemic need to make changes in treatment poli-cy on the basis of regular monitoring of the response of the malaria parasite to treatment with chloro-quine. The standards for measuring chloroquine resistance are WHO tests for drug efficacy in vivo. However, these tests require 2–4 weeks to perform and are difficult to interpret in areas in which malar-ia is endemic and transmission is high. In addition, they require multi-site, representative and repeat-ed studies with samples of sufficient size to allow changes to be detected. Alternatives have includ-ed a variety of tests in vitro (Desjardins et al., 1979; Druilhe et al., 2001), all of which involve the draw-ing of venous blood and some level of parasite culti-vation, which has high rates of assay failure, even in highly equipped laboratories and in expert hands. Therefore neither the tests in vivo nor the current-ly available tests in vitro are suitable for large-scale epidemiological surveys or in emergency situations, such as during malaria epidemics, in war zones or for displaced populations.

2. EPIDEMIOLOGICAL SURVEILLANCE USING MOLECULAR MARKERS OF RESISTANCE

2.1 Surveillance of chloroquine resistance

Point mutations in the gene encoding a P. falciparum membrane transport protein, pfcrt, have recent-ly been shown to be the primary molecular basis of resistance to chloroquine (Fidock et al., 2000). We have developed molecular methods to detect these mutations in field samples from Mali. We also showed that the mutation from lysine to threonine at position 76 (K76T) of pfcrt was absolutely select-ed in the presence of chloroquine in vivo, and that the presence of this mutation before treatment was strongly associated with failure of chloroquine in vivo (Djimdé et al., 2001a). The K76T mutation in pfcrt was present at a baseline prevalence of 40.5% in the human population, while only 14.5% of cases exhibited resistance in vivo, suggesting that this mutation could not be used to predict resistance to chloroquine on a case-by-case basis. However, the role of markers for epidemiological surveillance of drug resistance needs to be investigated.

In an attempt to validate assays for pfcrt K76T muta-tion as a tool for epidemiological surveillance of drug resistance, we repeated the studies described above on an annual basis for 3 years and added an addi-tional site that had different malaria epidemiologi-cal features as compared with both of the previous sites. We found stable age-adjusted genotype-resis-tance indices (GRIs) (Figure 1). This indicates that once a GRI has been determined for a given country or region, one could use simple methods to collect samples of blood spotted onto filter papers (Plowe et al., 1995), send them for analysis in a central lab-oratory and use the prevalence of the molecular marker to infer rates of clinical resistance from sim-ple cross-sectional molecular surveys (Djimdé et al., 2001b). This model is currently being validated in Mali and other African countries.

GRI = Pm/PDR => PDR = Pm/GRI

where

Pm = Prevalence of molecular markerPDR = Prevalence of drug resistanceGRI = Genotype-resistance index

Figure 1. The genotype-resistance index model


2.1 Monitoring resistance during malaria epidemics

Malaria epidemics occur in areas into which malar-ia has been recently introduced (Verdrager, 1995), in highlands or desert areas (Omar et al., 2001), or in situations in which naive populations such as ref-ugees, economic migrants or military troops have moved to an area affected by malaria (Srivastava et al., 1995; Sanchez et al. 2000). The timely detec-tion of resistance to antimalarial drugs in such situ-ations is critical, as unknown resistance could lead to a dramatic increase in mortality and morbidity caused by malaria. These situations typically require rapid diagnosis, to which the current WHO assays for resistance in vivo or in vitro are not amenable. Furthermore, in some cases it is simply impossible, for security reasons, to leave a team on the ground for extended periods.

In September 1999, after high rainfalls, the district of Kidal in the Sahara desert in Mali experienced an epidemic of malaria. The government sent a team from the National Malaria Control Programme and researchers from the Malaria Research and Training Center to manage the epidemic. Because rebel move-ments were operating in the district at that time, the team had to work under military escort and could not spend more than a week on the ground. To mea-sure the efficacy of antimalarial drugs in the area, we collected blood spotted onto filter papers, as pre-viously described (Plowe et al., 1995). These sam-ples were sent to the Malaria Research and Training Center laboratory in Bamako, where they were ana-lysed by polymerase chain reaction (PCR) for the presence of molecular markers of resistance to chloroquine and sulfadoxine/pyrimethamine (the first- and second-line antimalarial drugs in Mali, respectively). A week later, preliminary results sug-gested that the molecular marker for resistance to chloroquine (pfcrt K76T) was highly prevalent in the area. In contrast, the molecular marker for resis-tance to sulfadoxine/pyrimethamine (mutation at codons 51, 59 and 108 of the gene encoding dihydro-folate reductase, DHFR 108+51+59, and mutation in codons 437 and 540 of the gene encoding dihy-dropteroate synthetase, DHPS 437+540) was absent (Djimde et al., 2004). These led us to recommend to the National Malaria Control Programme the use of sulfadoxine/pyrimethamine rather than chloro-quine in this health district.

3. DISCUSSION AND CONCLUSION

The example described here represents the first use of molecular markers of resistance to antimalarial drugs as a means of advising policy in a real-life sit-

uation. In this case, given the need for a speedy eval-uation of drug resistance and the lack of security in the area, this was the only way to measure resis-tance to antimalarial drugs. The model may also be applicable to other emergency situations, such as refugee camps, and where there has been mass movement of naive populations into an area affect-ed by malaria. Other molecular markers of drug resistance, such as those recently described for sulf-adoxine/pyrimethamine (Kublin et al., 2002), could also be incorporated. This example highlights the need to intensify research into the elucidation of the molecular mechanism of resistance to other current-ly available antimalarials, including quinine, amo-diaquine, artemisinine derivatives, mefloquine and halofantrine.

References

Barat LM et al. (1998). A systematic approach to the development of a rational malaria treatment policy in Zambia. Tropical Medicine and International Health, 3:535–542.

Desjardins RE et al. (1979). Quantitative assessment of antimalarial activity in vitro by a semiautomat-ed microdilution technique. Antimicrobial Agents and Chemotherapy, 16:710–718.

Djimdé A et al. (2001a). A molecular marker for chlo-roquine-resistant falciparum malaria. New England Journal of Medicine, 344:257–263.

Djimdé A et al. (2001b). Application of a molecular marker for surveillance of chloroquine-resistant falci-parum malaria. The Lancet, 358:890–891.

Djimdé AA et al. (2004). Molecular diagnosis of anti-malarial drug resistance in epidemics and war zones. Journal of Infectious Diseases (in press).

Druilhe P et al. (2001). A colorimetric in vitro drug sensitivity assay for Plasmodium falciparum based on a highly sensitive double-site lactate dehydrogenase antigen-capture enzyme-linked immunosorbent assay. American Journal of Tropical Medicine and Hygiene, 64:233–241.

Fidock DA et al. (2000). Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance. Molecular Cell, 6:861–871.

Kublin JG et al. (2002). Molecular markers for failure of sulfadoxine-pyrimethamine and chlorproguanil-dapsone treatment of Plasmodium falciparum malaria. The Journal of Infectious Diseases, 185:380–388.


Omar SA et al. (2001). Plasmodium falciparum in Kenya: high prevalence of drug-resistance- associated poly-morphisms in hospital admissions with severe malar-ia in an epidemic area. Annals of Tropical Medicine and Parasitology, 95:661–669.

Plowe CV et al. (1995). Pyrimethamine and proguanil resistance-conferring mutations in Plasmodium fal-ciparum dihydrofolate reductase: polymerase chain reaction methods for surveillance in Africa. American Journal of Tropical Medicine and Hygiene, 52:565–568.

Sanchez JL et al. (2000). Malaria in Brazilian mili-tary personnel deployed to Angola. Journal of Travel Medicine, 7:275–282.

Srivastava HC et al. (1995). Epidemiological obser-vations on malaria in villages of Buhari PHC, Surat, Gujarat. Indian Journal of Malariology, 32:140–152.

Wellems TE & Plowe CV (2001). Chloroquine-resistant malaria. The Journal of Infectious Diseases, 184:770–776.

Verdrager J (1995). Localized permanent epidemics: the genesis of chloroquine resistance in Plasmodium falciparum. Southeast Asian Journal of Tropical Medicine and Public Health, 26:23–28.


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Annex 10 WORKING PAPER: Strategies for improved diagnostics for malaria, including rapid diagnosis


STRATEGIES FOR IMPROVED DIAGNOSTICS FOR MALARIA, INCLUDING RAPID DIAGNOSIS

John W. Barnwell, Louise Causer and Peter B. BlolandMalaria BranchDivision of Parasitic DiseasesNational Center for Infectious DiseasesCenters for Disease Control and PreventionAtlanta, Georgia, USA

1. INTRODUCTION

Early, prompt and accurate diagnosis and treat-ment is crucial to the management of morbidity and mortality caused by malaria and is one of the main interventions used in the global control of malaria. However, poor diagnosis continues to hinder mea-sures for the control of malaria. Rising drug costs resulting from the need to use newer medications or combination therapy, and recognition of the inac-curacy of clinical diagnosis are increasing demand for the demonstration of parasitaemia prior to ther-apy. The diagnosis of malaria was most recent-ly addressed in a report entitled New perspectives: malaria diagnosis 2000 (WHO, 2000), developed from the proceedings of a WHO/USAID informal consul-tation held in late 1999. This report summarized the current state of malaria diagnostics, explored issues on roles of rapid diagnostic tests (RDTs) (commonly referred to as “dipsticks”) in strategies for the diag-nosis and control of malaria, and defined certain research needs and standards for the wider imple-mentation of RDTs in the management of malaria. It was generally agreed that RDTs have a place as an alternative to diagnosis based on clinical grounds or microscopy in some situations, in particular, where good quality microscopy services cannot be readily provided. In the 3 years since this report came out, there have been some changes that may alter the rec-ommendations and conclusions reached, but there has also been limited progress in addressing many of the recommendations made for further applied and operational research.

2. CURRENT APPROACHES TO THE DIAGNOSIS OF MALARIA

2.1 Clinical diagnosis

Clinical diagnosis is the most widely applied meth-od for the diagnosis of malaria. Among the many

clinical signs and symptoms associated with malar-ia and used in diagnosis, the most prominent is fever, which is often associated with chills, perspi-ration, anorexia, headaches, vomiting and malaise. Additional signs indicating severe malaria include confusion or drowsiness. However, although clin-ical diagnosis is sensitive, it is also poorly specific. Nevertheless, it is often the only feasible approach in many circumstances, such as in rural areas and at peripheral health-care facilities and in areas of high endemicity. The approach requires trained personnel but is inexpensive to perform, and requires no spe-cialized equipment. The major disadvantage relates to its low specificity. Over diagnosis and subsequent over treatment of patients leads to increased drug pressure, which may facilitate the development of drug resistance. This may increase costs, particular-ly with newer, more expensive drugs, and expose patients to the unnecessary risk of adverse events.

2.2 Microscopy

In the laboratory, conventional light microscopy is the established “gold standard” for the confir-mation of malaria and has changed little over 100 years. Microscopy requires trained, skilled techni-cians, good supervisory personnel and good equip-ment (microscopes, reagents) in order to achieve “gold standard” sensitivities and specificities. A skilled technician can detect parasites at densi-ties as low as 5–10 parasites per µl of blood (WHO, 1990). However, the detection capabilities of a typi-cal microscopist might be more realistically placed at 100 parasites per µl of blood (WHO, 1988).

Microscopy can be used to quantify and characterize species and circulating stage, providing indices to guide therapy. This method is relatively inexpensive at US$ 0.12–0.40 per slide in countries where malar-ia is endemic (WHO, 2000). The necessary skills and equipment can be shared with other disease control programmes, further minimizing costs. In addition, unlike other diagnostic modalities, microscopy pro-vides a permanent record of results. Unfortunately, microscopy can be time-consuming (requiring at least 60 minutes from time of sample collection to diagnosis), and clinicians may make treatment deci-sions without the benefit of the results. In general, use of microscopy is often very limited at peripher-al health facilities as a result of personnel and other resource constraints.

2.3 Quantitative buffy coat and fluorochromes

DNA-binding fluorochromes can be used to aid the detection and quantification by microscopy of par-


asites in blood smears and in the layer of erythro-cytes (“buffy coat”) in centrifuged blood samples. However, such modifications increase the cost of microscopy and require special equipment, electrici-ty, and additional supplies.

2.4 Polymerase chain reaction

Analysis of blood samples by amplification of par-asite-specific nucleic acids by nested and real-time polymerase chain reaction (PCR) is reported to be highly sensitive and specific. The technique requires highly trained personnel, and is both time- and resource-intensive. Special equipment, labile reagents and specialized testing environments are also required, and these are not routinely available in the field.

2.5 Rapid diagnostic tests

Rapid diagnostic tests (RDTs) use immunochromato-graphic methods to detect antigens derived from malaria parasites in lysed blood. Tests that are cur-rently available rely on detection of the following:– Histidine-rich protein II (HRP-II) (Howard et al.,

1986), a water-soluble protein produced by tro-phozoites and young (not mature) gametocytes of P. falciparum only;

– Parasite lactate dehydrogenase (pLDH) (Makler & Hinrichs, 1993) produced by asexual and sex-ual stages (gametocytes) of parasites of P. falci-parum and non-falciparum species;

– Aldolase, another enzyme in the glycolytic path-way that is present in all four species of malar-ia parasite, is targeted in kits that also combine detection of HRP-II antigen of P. falciparum together with an unspecified “pan-malarial” antigen of the other species.

RDTs have generally been reported to achieve sen-sitivities of > 90% in the detection of P. falciparum at densities at or above 100 parasites/µl of blood. Below this level, sensitivity decreases markedly. Although less extensively studied, kits for the detec-tion of pLDH achieve sensitivities for P. vivax com-parable to those for P. falciparum, as indicated by past investigations. The specificity of RDTs is uni-formly high (mostly > 90%) (WHO, 2000). Previous issues related to cross reactivities and false-pos-itive results, particularly with the earlier tests for HRP-II, have reportedly been corrected. Since RDTs detect circulating antigens, they may detect infec-tion with P. falciparum even when the parasites are sequestered deep in the vascular compartment and thus undetectable by microscopic examination of a peripheral blood smear.

Among the advantages of RDTs are their ease of use and interpretation. They do not require any electrici-ty or special equipment, but an appropriate clinic or lab environment may be helpful. It has been stated that only minimal, brief training is necessary with good retention of skills and minimal inter-user vari-ability, but more recent studies cast some doubt on this blanket statement. Test kits can be shipped and stored under ambient conditions, but these ambient conditions must be within a defined range.

RDTs that detect only HRP-II are of limited use in areas where species other than P. falciparum are co-endemic and cause a significant proportion of dis-ease. Kits that detect LDH from both P. falciparum and non-falciparum species cannot differentiate between P. vivax, P. ovale and P. malariae, nor can they distinguish pure infections with P. falciparum from mixed infections that include P. falciparum. Neither type of RDT is able to differentiate between sexual and asexual stages. Persistent positive results with tests for HRP-II, up to 7–14 days after chemotherapy and parasite clearance (Shiff et al., 1993), place some limits on the usefulness of these tests in monitor-ing response to therapy and indicating drug failure or drug resistance. RDTs are not quantitative, and thus are unable to provide information of prognos-tic importance. This also limits their suitability for use in trials of therapeutic efficacy. RDTs are gener-ally more expensive per test than microscopy, rang-ing from US$ 0.60 to US$ 2.50 or more, depending on the marketing area (WHO, 2000).

More recent use and evaluation of these tests in remote areas and/or under conditions of operation-al use have reported sensitivities and specificities well below those originally reported (Rubio et al., 2001; Huong et al., 2002; Mason et al., 2002). These results have prompted questions related to a range of issues, including casting doubt on the accuracy of RDT-based diagnosis in remote areas, the stability and robustness of these tests in their current formats under field conditions, and in particularly issues related to quality control during production. The past few years have also witnessed a rapid expan-sion in the range of product maufacturers, and the disappearance of some products upon which early evaluations of RDTs were based. There is clearly also a need to clarify the position of RDTs in the manage-ment and control of malarial disease.

3. SUMMARY OF CURRENT DIAGNOSTIC PRACTICES

Several factors determine the choice of diagnos-tic practices to be used in a given geographic area,


including level of endemicity, prevalence and type of drug resistance, geographic accessibility, social/economic characteristics, health infrastructure, and the available diagnostic tools. The following sum-marizes the state of current diagnostic practices, which has changed little from the time of the 1999 WHO/USAID informal consultation report on malaria diagnosis (WHO, 2000).

In areas of high transmission, malaria occurs fre-quently and predominantly in young children and access to health care is often difficult. Clinical diag-nosis is used widely; cases in which this initial diag-nosis should be confirmed with microscopy or RDTs, depending on the situation, include: – Cases of suspected severe malaria, to guide ini-

tial therapy; – Persistence of parasites needs to be proved to

confirm treatment failure (microscopy);– Urban private-sector health providers;– Multidrug resistance where treatment based on

clinical diagnosis alone ceases to be rational pol-icy.

In areas of low to moderate transmission, malar-ia occurs less frequently and in all age groups. Multidrug resistance has developed in some of these areas. Laboratory confirmation of malaria is thus the goal. Microscopy diagnosis is generally avail-able at the central level, but is unreliable or absent in remote areas.

Situations benefiting from use of RDTs are:– Highly mobile populations in remote areas (for

example in northwest Thailand, Cambodia, India, and Brazil);

– In areas affected by multidrug resistance, for which the treatments are more expensive than the test;

– Prevention and management of severe malaria, i.e. early diagnosis and treatment.

Other special situations that could benefit from RDTs include complex emergencies, malaria epi-demics, malaria in travellers returning to countries where malaria is not endemic, stand-by emergen-cy self-diagnosis in travellers, and front-line at-risk active duty military (or organized workforces).

4. ISSUES AND RESEARCH DIRECTIONS

As noted above, RDTs have a number of potential applications in disease management and control for malaria. The major application in terms of test volumes and impact on disease is that of improv-ing diagnostic accuracy in areas that are remote from

facilities with microscopy and expertise. However, wherever possible, microscopic equipment should be maintained and microscopists should be trained. Nevertheless, a need for RDTs is apparent and these devices are already widely used for diagnosis of malaria in many countries. Changes in treatment policies to use of more expensive multidrug regi-mens will increase the importance of obtaining an accurate diagnosis based on demonstration of para-sitaemia prior to treatment and, along with a provi-sion of funds to national malaria control programmes from the Global Fund to Fight AIDS, Tuberculosis and Malaria will further increase the use of RDTs. An informal assessment of the current status of RDTs in malaria control and progress since the previous WHO informal consultation in 1999 (WHO, 2000) was held recently in Manila, Philippines (WHO, 2003); steps were defined to address a number of unresolved issues and research objectives in regard to the wide-spread use of RDTs by malaria control services.

4.1 Technical characteristics of rapid diagnostic tests and developmental research needs

RDTs should provide diagnostic results that are at least as accurate as those derived from microsco-py performed under routine field conditions. To meet that ideal standard, RDTs must fulfil specif-ic technical characteristics as specified by the pre-vious consultation in 1999 (WHO, 2000). Sensitivity is the most critical issue, since false-negative results can result in failure to treat a potentially fatal dis-ease; sensitivity should be close to 100% or at least 95% at 100 parasites per µl of blood for detection of P. falciparum, and ideally also P. vivax. RDTs should be able to detect all four species of malaria parasite that infect humans, or at least to differentiate P. fal-ciparum from the other species. Specificity should be > 90% for detection of malaria. Another preferred characteristic of malaria RDTs would be a shelf-life of 18 months to 2 years at 40˚C. These are ideal spec-ifications and it is likely that the specified perfor-mance capabilities will not be met in the near future without additional developmental research.

Specific developmental research needs

– Identification of new target antigens, taking advantage of the newly available genomic and proteomic data. Presently marketed RDTs tar-get one or a combination of P. falciparum-specific pLDH, pan-specific pLDH, HRP-II, or pan-spe-cific aldolase. Development of tests that dis-tinguish between non-falciparum species is worthwhile and will have increasing applica-tion in the future, if drug resistance of non-falci-parum species becomes more widespread.


– Improvement in current test performance char-acteristics through enhanced formats and pro-duction of robust capture antibodies, in order to consistently obtain a minimum sensitivity threshold of greater than 95% at 100 parasites per µl of blood in all four species. Sensitivity for non-falciparum species in particular requires further improvement. Specificity, although less important, should remain at a high level (> 90%) in order to direct therapy with accuracy. Early field trials of RDT products demonstrated their potential for achieving high sensitivity and specificity (Moody et al., 2002) but several recent trials have reported sensitivity and specificity below that required for operational use (Huong et al., 2002).

– Improvement of existing blood transfer devic-es. Transfer of the correct volume of blood to the strip is a critical step that can lead to false results. Improving accuracy and ease of use of blood transfer devices will lead to improved test performance.

Quality assurance and quality control needs

While a number of countries (Thailand, Cambodia, South Africa) are already basing their public-sector diagnosis of malaria in remote areas on RDTs, vari-ation in test results on large-scale implementation has resulted in some uncertainty as to their suitabili-ty and reliability. In this regard, relatively few coun-tries have any mechanisms in place to monitor the quality of RDT performance. Additionally, the range of available malaria RDTs has changed and expand-ed rapidly since 1999. Twenty-five or more brand-name products are available commercially now, or will be available in the near future. The majority of these target P. falciparum only. Six products available in or prior to 1998 are no longer on the market. The development of a comprehensive quality assurance and control programme(s) is essential to ensure that test quality is maintained, reducing the likelihood of misdiagnosis and maintaining confidence of health-care service providers and consumers.

The following are required:– The most appropriate methods/systems for

maintaining and monitoring quality of RDTs before and during distribution and use should be determined, along with directions for future research on RDT quality assurance systems.

– Development of a bank of reagents and a net-work of quality control (QC) testing sites. Parasite-based QC panels from geographical-ly-diverse areas, to allow for possible regional variations in antigenicity, should be developed and made available to manufacturers and other

interested parties. Sensitivity of some tests could vary in geographically distinct areas.

– Large-scale multi-site phase III/IV field trial(s) to determine the best/most appropriate RDT products for field use, to determine the main issues surrounding deployment of RDTs that may need to be addressed by further research, and to define minimum standards/guidelines appropriate for other RDT field trials.

Specific operational research needs

The increased use of combination therapies increas-es the importance of demonstrating parasitaemia prior to treatment. This enlarges the need for opera-tional research to guide large-scale implementation of RDT-based diagnosis. There is a need to:– Evaluate the ease of use and accuracy of existing

blood transfer devices and dispensers of buffer solution in the hands of the likely end-users.

– Evaluate the impact of package insert formats. Improved insert formats, including diagrams and text, adaptable to different cultural back-grounds, should be developed.

– Evaluate the impact of the large-scale introduc-tion of RDTs at a national level on diagnosis and treatment of malaria, and in terms of impact on quality of clinical care, cost–effectiveness, sav-ings in drug costs, improved patient manage-ment and health provide treatment practices.

– Assess, through qualitative and quantita-tive research measures, what factors affect the choice of a diagnostic test, its implementation or expansion of usage at a national level.

– Assess the impact of the introduction of a qual-ity assurance scheme for RDTs on health-care service delivery, including the quality of train-ing materials.

– Assess different distribution systems to remote areas in order to ensure a regular supply of RDTs that are within their expiry date and in a fit condition for use, including temperature monitoring and evaluation of the feasibility of developing low-cost temperature monitors for packaging with RDTs.

– Investigate the practicability of using positive-control wells containing target antigens at a pro-vincial or district level for quality control.

– Assess the cost–effectiveness and cost–benefit of RDTs and diagnostic alternatives with regard to epidemiology, treatment costs, availability of alternatives, case load, the aims of the interven-tion, and the cost of the RDT itself.

– Assess the present use of RDTs in the private sector, the potential for expansion, and the like-ly regulatory problems, to guide development of policy to encourage responsible use in this sector.


References

Howard RJ et al. (1986). Secretion of a malaria histi-dine-rich protein (Pf HRP II) from Plasmodium falci-parum-infected erythrocytes. Journal of Cell Biology, 103:1269–1277.

Huong NM et al. (2002). Comparison of three anti-gen detection methods for diagnosis and therapeu-tic monitoring of malaria: a field study from southern Vietnam. Tropical Medicine and International Health, 7:304–308.

Makler MT & Hinrichs DJ (1993). Measurement of the lactate dehydrogenase activity of Plasmodium fal-ciparum as an assessment of parasitemia. American Journal of Tropical Medicine and Hygiene, 48:205–210.

Mason DP et al. (2002). A comparison of two rapid field immunochromatographic tests to expert micros-copy in the diagnosis of malaria. Acta Tropica, 82:51–59.

Moody A (2002). Rapid diagnostic tests for malaria parasites. Clinical Microbiology Reviews, 15:66–78.

Rubio JM et al. (2001). Limited level of accuracy pro-vided by available rapid diagnosis tests for malaria enhances the need for PCR-based reference laborato-ries. Journal of Clinical Microbiology, 39:2736–2737.

Shiff CJ, Premji Z & Minjas JN (1993). The manual Parasight-F test. A new diagnositic tool for Plasmodium falciparum infection. Transactions of the Royal Society of Tropical Medicine and Hygiene, 87:646–648.

WHO (1988). Memorandum from a WHO meeting. Bulletin of the World Health Organization, 66:575–594.

WHO (1990). Severe and complicated malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 84(Suppl. 2):23–25.

WHO (2003). Malaria rapid diagnostics: making it work. Meeting report 20–23 January 2003. Manila, World Health Organization (RS/2003/GE/05[PHL])

WHO/United States Agency for International Development (2000). New perspectives: malaria diag-nosis. Report of a joint WHO/USAID informal consul-tation, 25–27 October 1999. Geneva, World Health Organization (WHO/CDS/RBM/2000.14, WHO/MAL/2000.1091; http://whqlibdoc.who.int/hq/2000/WHO_CDS_RBM_2000.14.pdf, accessed 27 April 2004).


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Annex 11 WORKING PAPER: Plasmodium falciparum – a genome revealed


PLASMODIUM FALCIPARUM: A GENOME REVEALED

Dyann WirthDepartment of Immunology and Infectious DiseasesHarvard School of Public HealthBoston, MA, USA

1. INTRODUCTION

The sequencing of the Plasmodium falciparum genome, described in October 2002 in Nature, repre-sents a milestone – this is the first parasite genome to be published. It was accomplished by a consor-tium of laboratories and funding agencies, and the published reports are a testament to the success of this international collaboration (Carlton et al., 2002; Florens et al., 2002;Gardner et al. 2002a, 2002b; Hall et al., 2002; Hyman et al., 2002; Lasonder et al., 2002). This is a major achievement for the field of malaria research and provides key insights into the biology of the organism that causes the most deadly form of this important disease. Despite massive efforts to eradicate the disease in the 1950s and early 1960s, there are more people with malaria in Africa today than at any other time in history. More than 500 mil-lion people worldwide are infected with malaria and one-quarter of the world’s population is at risk of infection. More than one million children die of malaria each year, most of them in Africa; those who survive chronic infection suffer from a combination of anaemia and immune suppression that leaves them vulnerable to other fatal illnesses. Drug resis-tance in the parasite is now widespread, and further compromises prevention and treatment strategies.

1.1 Features of the parasite genome

Malaria has confounded some of the best minds of this century. A hundred years after the discovery that mosquitoes transmit malaria, we still do not know enough about the disease to defeat it perma-nently. The organism that causes malaria has a com-plex life cycle; it exists as an intracellular parasite in the human host and as an extracellular parasite in the mosquito vector. One of the most fascinating features of malarial infection concerns the human immune response – there is an extensive humoral and cellular response yet, in the natural situation, this immune response is not protective. The para-site genome gives us some hints about the mecha-nisms by which this response is evaded. Now the challenge to all is how to use this information. What have we learned and where do we go from here?

First, what aspects of the P. falciparum genome are unique? Probably the most striking genomic fea-ture concerns the regions located at the end of each chromosome (telomeres). There are a very limited number of gene types – genes encoding surface anti-gens present in multiple copies, the var, rifin and ste-vor genes (Gardner et al., 2002a). These genes are subject to gene conversion between chromosomes and are the major variant antigens in the organism. There is also a complex arrangement of different tel-omere-specific sequences. These may act to facilitate genetic exchange between chromosome ends, either through physical association or as templates for the initiation of recombination and conversion (Freitas-Junior et al., 2000; Horrocks et al., 2002; Peters et al., 2002). This in turn leads to the formation of new antigenic types and to changes in the expression of different variant antigens.

Comparison of the genomes of P. falciparum and P. yoellii shows that the general structure of the ends of the chromosomes ends is conserved, but interesting-ly, the genes that encode the variant surface antigens in P. falciparum are absent from P. yoellii (Carlton et al., 2002). In contrast, several other antigen and sur-face proteins are homologous between P. falciparum and P.yoellii. A new family of variant genes, origi-nally described in P. vivax, is present in P. yoellii (del Portillo et al., 2001). The vir gene homologues, the yir genes, are present in subtelomeric locations and also represent a multigene family. It is tempting to speculate that the yir and var genes have a common function, but the sequence divergence in the protein-coding regions is such that no functional similarity can be deduced. Since the discovery of the var genes, their role in cytoadherence has been the primary focus of research on their function, yet erythrocytes infected with P. vivax or P. yoellii are not sequestered in the same way and do not display similar cytoad-herence properties. It is interesting to note that in the proteomic analysis of P. falciparum at the tro-phozoite stage, no single abundant PfEMP1 protein (product of the var gene) was detected, yet at the sporozoite stage, peptides derived from multiple var genes (51% of the predicted var genes) were detect-ed (Florens et al., 2002; Lasonder et al., 2002). These results point to alternate functions for the products of the var genes and warrant further investigation.

2. METABOLISM AND DRUG DEVELOPMENT

The long-term goal of the malaria parasite genome project is to apply new knowledge about the genome to the control of infection and disease. At the level of primary analysis, knowledge of the genome sequence provides enormous opportunity to pursue


the development of new drugs through the iden-tification of new, potentially unique or differential targets. Even before the completion of the sequenc-ing of the genome, new drug targets were identified through homology searches of the partially assem-bled sequence data (Jomaa et al., 1999). However, the availability of the complete sequence will now allow the elucidation of metabolic pathways and the identification of key weaknesses in the metabol-ic processes of the parasite. The sequence also pro-vides immediate insight into potential receptor and signalling pathways, which have proven to be excel-lent targets for the development of small-molecule drugs in mammalian systems.

There are some unexpected results. The most striking is the apparent absence in the P. falciparum genome of key proteins required for mitochondrial metabo-lism and energetics. For example, no predicted gene could be identified that encodes Fo subunits a and b of the ATP syntase. Similarly, the genome lacks genes that encode components of a conventional NADH dehydrogenase complex I (Gardner et al., 2002a). The implications could be important in that P. falciparum may possess novel proteins or mecha-nisms for the generation of energy; there is a clear research agenda here and potential both to increase our understanding of the biology of the organism and to identify novel drug targets. In sporozoites and gametocyes, peptides from enzymes involved in the mitochondrial tricarboxylic acid (TCA) cycle and oxidative phosphorylation have been detect-ed, consistent with the presence of fully functional mitochondria in the organism at these stages of the life cycle (Florens et al., 2002; Lasonder et al., 2002).

Another striking feature is the number of predict-ed proteins associated with the apicoplast; approx-imately 10% of all the predicted genes are putative apicoplast proteins (Gardner et al., 2002a). This organelle has already been identified as being impor-tant in fatty acid, isoprenoid and haem biosynthe-sis, however, analysis of the genome will now allow identification of other putative functions. The high degree of conservation of the 35 kb genome of this organelle within the apicomplexan family is indica-tive of an important function, and drugs specifically targeted to this organelle effectively kill the parasite (Waller et al., 1998; Ralph et al., 2001). Thus a better understanding of this organelle may lead to the dis-covery of novel drug targets.

Compared with S. cerevisiae, a free-living eukaryote, P. falciparum has a limited repertoire of transporters (Gardner et al., 2002a); entire classes of transporters seem to be absent from the parasite genome. As is possible with all gene models, it may be that some

genes in this class have not been identified by the gene prediction algorithms. Alternatively, the para-site may use previously identified pores or channels for the acquisition of nutrients (Haldar, 1998; Dsai et al., 2000; Kirk, 2000). No candidate genes for such molecules have been identified in the genome anno-tation, and resolution of this question awaits further experimentation and analysis.

3. PARASITE DEVELOPMENT AND GENE REGULATION

During its life cycle, Plasmodium undergoes several developmental switches – one of the most dramatic is that of sexual differentiation and gamete formation. A single genome is totipotent – that is, it can make both female and male gametes. Understanding the determinants of sexual differentiation is important both from a fundamental biology standpoint and for the development of interventions. Transmission-blocking vaccines are already in the process of development and drugs that inhibit gametocyte development may be very important in prevent-ing epidemics. Of particular interest are the types of proteins found in gametocytes. Two publications have reported similar findings; both groups found relatively enhanced expression of proteins involved in protein synthesis and RNA processing, particu-larly in the female gametocytes. Interesting, proteins expressed in early zygotes do not seem to be pres-ent in gametocyes; however, the messenger RNA (mRNA) is abundant, consistent with the previous hypothesis of a major role for post-transcription-al regulation in the expression of gamete proteins (Kocken et al., 1998; Dechering et al., 1999). Together with the relatively limited number of genes found that are predicted to encode transcription factors, it is tempting to speculate that a major component of gene regulation in P. falciparum may be at the level of RNA processing and stability, similar to that dis-covered in other protozoan parasites. This presents a potentially unique target for drug or vaccine inter-ventions.

It is also of interest to note that gametocytes express a limited repertoire of previously identified variant antigens, including Pfemp1 and rifins. Gametocytes freely circulate and, presumably, are not seques-tered. This would imply that the subset of var genes expressed in gametocytes encode proteins that do not mediate sequestration; it would be interesting to examine these genes in comparison with those expressed at asexual blood stages of the parasite in order to gain insight into functional characteristics of this class of molecules.


4. GENE REGULATION

One of many unanswered questions concerns the means by which Plasmodium regulates gene expres-sion. The results of analysis of the genome sequence indicate that there are very few predicted transcrip-tional regulatory elements that are related to those in other organisms. Yet, on the basis of proteomic anal-ysis and many previous experiments, the abundance of proteins is tightly regulated. One of the challeng-es is to identify regulatory elements and genomics approaches may provide unique insights. Florens et al. (2002) used proteomics to identify groups of pro-teins whose regulation appears to be coordinated. Some are arranged in expression groups and others are expressed at the same time in distant locations of the genome. Comparison of these genes and their flanking sequences may provide useful insights into the mechanisms of gene regulation. In terms of protein translation, the parasite appears to have evolved a very efficient and non-redundant system. It is known that the ribosomal genes are present as a small number of single-copy genes and examina-tion of the sequence of the genome has shown that genes encoding transfer RNAs (tRNAs) also lack the redundancy found in other organisms.

5. POPULATION DIVERSITY AND COMPARATIVE GENOMICS

The availability of the entire sequence of the genome now provides the unique opportunity to examine the population structure of P. falciparum. There is a paradox in that some genes, such as that encoding merozoite surface protein-1 (MSP-1), are of ancient origin (dating from approximately the time of diver-gence of humans and primates), while other genes are essentially monomorphic and indicative of a more recent origin, with estimated dates of origin ranging from 10 000 to 150 000 years ago (Baum et al., 2002; Mu et al., 2002; Volkman et al., 2001). Resolution of this paradox is now possible and extensive single nucleotide polymorphism (SNP) mapping of the genome of P. falciparum from differ-ent geographic locations and with different pheno-types will provide the necessary data (Volkman et al., 2002). Comparison of the full genomic sequence of parasites isolated directly from an infected person should also provide key insights into those regions of the chromosome that are required for survival of the parasite in vivo.

Similarly, comparative genomics of other parasite species will provide important information. The most striking feature arising from the compari-son of the genomes of P. yoellii and P. falciparum is the degree of synteny and the large percentage of

shared genes, particularly genes encoding house-keeping functions. The sequence similarity, howev-er, is confined to protein-coding regions. Intergenic regions are not conserved and synonomous chang-es within coding regions are saturated. Interestingly, the sequences of genomes of these two parasite spe-cies are considerably more divergent than those of humans and rodents (Carlton et al., 2002). This is perhaps indicative of the extent of selection in the parasite life cycle, including immune selection in the mammalian host and biological selection in the insect vector.

6. OF MICE, MEN AND MOSQUITOES

The most exciting aspect of this work is its relation-ship to other work in the field. The sequence of the Anopheles gambiae genome was published in October 2002; draft sequences for the human and mouse genomes were already available. The genomes of all the players in this complex life cycle are thus acces-sible for analysis. The population structure of these three organisms can give us key insights into impor-tant biological functions. Human genes associated with reduced susceptibility to malaria have already been identified and more such genes are likely to be recognized after closer examination of different human populations and with the greater precision offered by the availability of the genome sequence. Several genes in P. falciparum that are highly genet-ically diverse are the targets of the human immune response and several others are likely to be identi-fied. Analysis of the Anopheles gambiae genome will provide similar insights.

Selection and co-evolution have produced the cur-rent extant populations of parasites, hosts and vectors. Decoding the information in the genome to reveal new biological insights is the challenge and the opportunity for the scientific community. Ultimately, we must use this information to reduce the burden of malarial disease. Every 40 seconds, a child dies of malaria, a disease that is preventable and treatable. New knowledge and new interven-tions are needed and these discoveries provide the framework.

References

Baum J, Ward RH & Conway DJ (2002). Natural selec-tion on the erythrocyte surface. Molecular Biology and Evolution, 19:223–229.

Carlton JM et al. (2002). Genome sequence and com-parative analysis of the model rodent malaria parasite Plasmodium yoelii yoelii. Nature, 419:512–519.


Dechering KJ et al. (1999). Isolation and functional characterization of two distinct sexual-stage-specific promoters of the human malaria parasite Plasmodium falciparum. Molecular and Cellular Biology, 19:967–978.

del Portillo HA et al. (2001). A superfamily of var-iant genes encoded in the subtelomeric region of Plasmodium vivax. Nature, 410:839–842.

Desai SA, Bezrukov SM & Zimmerberg J (2000). A voltage-dependent channel involved in nutrient uptake by red blood cells infected with the malaria parasite. Nature, 406:1001–1005.

Florens L et al. (2002). A proteomic view of the Plasmodium falciparum life cycle. Nature, 419:520–526.

Freitas-Junior LH et al. (2000). Frequent ectop-ic recombination of virulence factor genes in telo-mericchromosome clusters of P. falciparum. Nature, 407:1018–1022.

Gardner MJ et al. (2002a). Genome sequence of the human malaria parasite Plasmodium falciparum. Nature, 419:498–511

Gardner MJ et al. (2002b). Sequence of Plasmodium falciparum chromosomes 2, 10, 11 and 14. Nature, 419:531–534.

Haldar K (1998). Intracellular trafficking in Plasmodium-infected erythrocytes. Current Opinion in Microbiology, 1:466–471.

Hall N et al. (2002). Sequence of Plasmodium falciparum chromosomes 1, 3–9 and 13. Nature, 419:527–531.

Horrocks P et al. (2002). Effect of var gene disrup-tion on switching in Plasmodium falciparum. Molecular Microbiology, 45:1131–1141.

Hyman RW et al. (2002). Sequence of Plasmodium falci-parum chromosome 12. Nature, 419:534–537.

Jomaa H et al. (1999). Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs. Science, 285:1573–1576.

Kirk K (2000). Malaria. Channelling nutrients. Nature, 406:949, 951.

Kocken CH et al. (1998). Precise timing of expres-sion of a Plasmodium falciparum-derived transgene in Plasmodium berghei is a critical determinant of sub-sequent subcellular localization. Journal of Biological Chemistry, 273:15119–15124.

Lasonder E et al. (2002). Analysis of the Plasmodium falciparum proteome by high-accuracy mass spectrom-etry. Nature, 419:537–542.

Mu J et al. (2002). Chromosome-wide SNPs reveal an ancient origin for Plasmodium falciparum. Nature, 418:323–326.

Peters J et al. (2002). High diversity and rapid change-over of expressed var genes during the acute phase of Plasmodium falciparum infections in human volunteers. Proceedings of the National Academy of Sciences of the United States of America, 99:10689–10694.

Ralph SA, D’Ombrain MC & McFadden GI (2001). The apicoplast as an antimalarial drug target. Drug Resistance Updates, 4:145–151.

Waller RF et al. (1998). Nuclear-encoded proteins tar-get to the plastid in Toxoplasma gondii and Plasmodium falciparum. Proceedings of the National Academy of Sciences of the United States of America, 95:12352–12357.

Volkman SK et al. (2001). Recent origin of Plasmodium falciparum from a single progenitor. Science, 293:482–484.

Volkman SK et al. (2002). Excess polymorphisms in genes for membrane proteins in Plasmodium falci-parum. Science, 298:216–218.


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Annex 12 WORKING PAPER: Prospective antimalarial drug discovery and development


PROSPECTIVE ANTIMALARIAL DRUG DISCOVERY AND DEVELOPMENT

Solomon NwakaMedicines for Malaria VentureGeneva, Switzerland

1. INTRODUCTION

Chemotherapy remains one of the key measures used to control the intolerable burden of malaria. With increasing resistance to currently available antimalarial drugs and little investment by pharma-ceutical companies in research and development for antimalarial drugs, there is an urgent need for new drugs. Drug discovery and development is complex and requires specialized expertise and significant financial resources. This expertise largely resides with pharmaceutical companies that have signifi-cantly disengaged from R&D for tropical diseases because of poor market incentives.

The efforts of the Special Programme for Research and Training in Tropical Diseases (TDR)/WHO and a few other organizations to bridge the gap that exists in research and development for tropi-cal diseases have been energized by the formation of new public–private partnerships focusing on the development of drugs, vaccines and diagnostics for some of these diseases. Public–private partnerships, exemplified by the Medicines for Malaria Venture (MMV) (Medicines for Malaria Venture, 2000, 2001) and the Malaria Vaccine Initiative (MVI), show that the concept works. In addition to the efforts of MMV, other partnerships are active in the develop-ment of new drugs against malaria, such as the part-nership between TDR, WHO, GlaxoSmithKline and the United Kingdom Department for International Development, which is currently developing Lapdap (chlorproguanil-dapsone). The Drugs for Neglected Diseases Initiative (DNDi) has been formed to con-tribute to these efforts. It should be mentioned that GlaxoSmithKline has dedicated their Tres Cantos facility in Spain to the discovery of new compounds for diseases of developing countries (mainly malaria and tuberculosis), and also that Sanofi have imple-mented the Impact Malaria programme. These are all welcome new developments in the efforts to con-trol tropical diseases. However, tropical or neglect-ed diseases are many and require different levels of assault. The disease burden could be reduced if the afflicted countries had the appropriate technologies

and know-how to produce the essential drugs that they urgently require.

This paper reviews the current status of antimalarial drug discovery and development, and proposes the need to build more capacity and infrastructure for drug R&D in countries in which malaria is endemic. The following topics are discussed:– Target profile of new antimalarial drugs, and

scientific opportunities for new drugs– Drug discovery and development process– Public–private partnerships: MMV product

portfolio and others.– Status of drug research and development in dis-

ease endemic countries: problems and pros-pects.

2. TARGET PROFILE FOR NEW ANTIMALARIALS, AND SCIENTIFIC OPPORTUNITIES FOR NEW DRUGS

Antimalarial drugs have saved many lives, but most of the available drugs are no longer effective due to the problem of drug resistance. Some of those that are still effective suffer from problems associat-ed with compliance and high cost. These problems have partly encouraged the production of counter-feit or diluted brands in developing countries.

In an effort to counteract (or delay) the development of resistance, the concept of combination therapy was introduced. This concept is based on the syn-ergistic or additive potential of two or more drugs to improve therapeutic efficacy and also to delay the development of resistance to individual compo-nents of the combination (Global Partnership to Roll Back Malaria, 2001).

Most of the drugs currently undergoing preclinical and clinical development are artemisinin combina-tion drugs (Lapdap/artesunate, pyronaridine/arte-sunate, piperaquine/ dihydroartemisinin [DHA] etc.) and improved versions of existing compounds, such as antifolates and quinolines. Although these classes of compounds are expected to deliver new drugs in the short term, one could argue that they have limited innovation and will not completely resolve the malaria problem. (It must be mentioned that the investment on discovering a fully synthet-ic version of artemisin [the so called synthetic per-oxide] is paying off as we now have a compound in this class in development.) The need for innova-tion will require more investments in drug discov-ery research to identify new classes of compounds.

The desire to overcome some of the liabilities of available antimalarial drugs makes the discovery of


new chemical entities even more challenging. It is desirable that new drugs designed for the treatment of uncomplicated malaria are:– efficacious against drug-resistant strains of the

parasite;– able to provide a cure within three days, to

ensure better compliance;– safe for small children and pregnant women;– formulated (mainly for oral use) and packaged

appropriately for tropical conditions; – affordable.

Other profiles include: drugs that can be used for intermittent treatment in pregnancy and in early infancy, as well as for severe and P. vivax malaria (including radical cure). There is also the prospect of combining new compounds into combination prod-ucts.

The good news is that technological and scientif-ic advances that could be exploited for the devel-opment of new antimalarial drugs have never been greater. The availability of the parasite, host and vec-tor genomes (see Annex 11) has given a boost to the search for new antimalarial drugs. However, genom-ic approaches need to link with chemistry and high-throughput screening before drugs can be delivered (Rosenthal, 2001; Ridley, 2002). Pharmaceutical com-panies can support the genomics efforts by provid-ing chemistry and high-throughput screening for the new drug targets being identified.

Researchers in academic institutions around the world are acquiring a better understanding of the drug development process, and thus improving efficiency in drug discovery research. In Africa, the desire of scientists and local pharmaceutical com-panies to get more involved in drug discovery and development research (with all its competitive advantages) is hindered by lack of infrastructure and adequate capacity.

3. THE PROCESS OF DRUG DISCOVERY AND DEVELOPMENT

In order for a new chemical entity to make it to mar-ket as a safe and effective drug, it must pass through a series of hurdles. The initial set of hurdles to over-come is passing from the different drug discovery stages to the preclinical phase. A target-based dis-covery programme progresses from target identifi-cation to validation, to hit generation largely from high-throughput screening, to lead optimization and a lead candidate (see Table I). These steps are all important (Ridley, 2002). Analysis of why drugs fail in the clinic shows that in 39% of cases it is due to biopharmaceutical issues such as bioavailability, absorption, distribution, metabolism and excretion (ADME) properties and formulation; and in 21% of cases due to toxicity (Lipinski et al., 1997). These issues are as important as efficacy, which contrib-utes to 29% of failures.

Table 1. Overview of the processes of drug discovery and development

Process Stage Explanation

Discovery Target identification/validation

Find and analyse a protein target or process that can affect the outcome of disease if perturbed

Assay development Develop a method to find what perturbs/inhibits the target

High-throughput screening Test a collection of molecules to find ones that have activity

Hit-to-lead Run further tests on selected molecules and begin optimization

Lead optimization Optimize molecules for relevant pharmaceutical activity

Preclinical Test molecules in an animal model of the disease and perform safety (toxicological) studies

Development Phase I Determine safety and dosing of the drug in humans

Phase II Obtain proof-of-concept for drug efficacy in humans

Phase III Characterize drug extensively in large-scale human trials

Registration File a new drug application with regulatory authorities

The processes are more complex than is presented; additional programmes such as scale-up and process chemistry, statistical analysis and dossier preparation are important parts of these processes.


Traditional screening for compound discovery involves cell-based screens to identify compounds with potential therapeutic activities. Currently avail-able antibacterial and antimalarial compounds in the clinic today have benefited from semi-rational opti-mization programmes based on compounds, often natural products, identified by whole-cell screening. Therefore, integration of the strengths of such tradi-tional screening techniques with target-based ratio-nal approaches should be enhanced. One does not talk of an antimalarial lead optimization programme without discussing animal models of malaria. This is helpful not only for defining the pharmacology and proof-of-concept studies of efficacy, but rodent models also provide more rapid feedback to medici-nal chemists on aspects such as oral activity of com-pounds. The human malaria parasites do not infect rodents and specific rodent malaria parasites such as P. berghei have been used. This has worked well for drugs without a specific enzyme target, such as chloroquine and artemisinins. These drugs are believed to target haem metabolism in the food vac-uole, which is similar in rodent and human malarial parasites. This scenario ceases to be true for enzyme targets where there are differences in the protein sequence, structure and inhibitory specificity. In the absence of sufficient similarity between P. berghei or another model and P. falciparum enzymes, one has to either rely on cell culture data combined with rapid pharmacokinetic evaluation or move to more expen-sive and low-throughput primate models that can sustain P. falciparum infection.

Once a compound has shown satisfactory activi-ty in in-vitro and in-vivo screens, it is subjected to detailed preclinical assessment, which evaluates drug metabolism, pharmacokinetics, and toxic-ity in animals. After successfully passing through the preclinical stage, the new chemical entity can progress to clinical development (see Table 1). In the United States, an investigational new drug approval (IND) needs to be obtained from the Food and Drug Administration before progressing to clinical trials. In Europe, the equivalent of an IND does not exist currently, however, discussions are underway to introduce it. The IND will then enter phase I (safety and tolerability in healthy volunteers); phase II (effi-cacy in a small number of patients); and phase III (efficacy in a large population of patients). Should the drug successfully pass all three clinical phases, it is submitted to regulatory authorities for approv-al as a new drug.

A significant factor that increases costs in drug development is the high failure rate of new chem-ical entities, resulting in unnecessary development costs. It has been estimated that about 1 in 5000

compounds make it from discovery to the preclini-cal stage, while 1 in 25 compounds that make it from the preclinical stage to IND stage will make it to the market. Efforts are directed at a new series of in vitro assays (some being developed) that serve as reliable indicators to minimize attrition rate of new chemical entities. These models are helpful in reduc-ing preclinical and clinical failure rates by attempt-ing to accurately evaluate efficacy and safety much earlier in the drug discovery process. Public–private partnerships or organizations targeting drugs for neglected diseases are encouraged to consider this as it results in significant savings in time, money and resources. MMV has established rigorous clin-ical candidate selection guidelines for its discovery projects that consider these factors before commit-ting to expensive clinical development. In addition, the competitive project selection process using sci-entific experts in drug discovery and development is hoped to make the attrition rate in the MMV port-folio better than the industrial average (Nwaka & Ridley, 2003).

4. PUBLIC–PRIVATE PARTNERSHIP: MEDICINES FOR MALARIA VENTURE AND OTHERS

The MMV example shows that the public–private partnership concept works. Within three years of operation, MMV has attracted pharmaceutical com-panies and strong academic researchers to partner in the search for new drugs. The result so far is the management of the largest antimalarial drug devel-opment portfolio ever assembled by a single organi-zation with the goal to discover, develop and deliver one new drug every five years (Figure 1). The MMV portfolio considers the need to improve on the lim-itations of currently available antimalarial drugs. It also recognizes both the need to produce drugs urgently for short-term impact and the need for innovation. As a result, its portfolio includes sever-al drug discovery projects that are likely to identify new classes within seven years and beyond (Figure 1). Some of these projects are “piggy backing” on compounds being developed for other indications by pharmaceutical companies to identify new chem-ical entities fast.

MMV activities are funded and supported by the following organizations: Bill and Melinda Gates Foundation, the Global Forum for Health Research, International Federation of Pharmaceutical Manufacturers (IFPMA), the Rockefeller Foundation, Roll Back Malaria, the Swiss Agency for Development and Cooperation, The Netherlands Ministry for Developmental Cooperation, United Kingdom Department for International Development, World


Bank, World Health Organization, Exxon Mobil Foundation, WHO/TDR, Wellcome Trust.

5. STATUS OF DRUG RESEARCH AND DEVELOPMENT IN DISEASE-ENDEMIC COUNTRIES: PROBLEMS AND PROSPECTS

A number of developing countries have the poten-tial to produce drugs for neglected diseases, but the capacity and capability to perform the spectrum of tasks from early discovery research through to pre-clinical and clinical development, dossier assembly and registration are fragmented and vary wide-ly from country to country (Olliaro & Navaratnam, 2002; Yuthavong, 2001; Nwaka & Ridley, 2003). Although developing drugs from scratch is clearly difficult, some institutions in developing countries, such as India, Brazil, China, Thailand, the Republic of Korea , South Africa and a few other countries in Africa, are able to produce existing and newly dis-covered compounds. Whether these countries have an infrastructure that meets overall international reg-ulatory standards needs to be clearly determined.

In the drug research and development chain, it is fair to say that some capacity and capability exist in the following areas: genomics, synthetic chemistry,

low-to medium-throughput compound screening, natural products screening, preclinical studies that do not comply with good laboratory practice (GLP), process chemistry, manufacture that does not com-ply with good manufacturing practice (GMP), for-mulation and clinical trials. The gaps in expertise in developing countries are most acute in the areas of high-throughput screening, lead optimization, pre-clinical and clinical development that complies with GLP, data management and dossier preparation, and, of course, the ability to perform the studies nec-essary to meet international regulatory standards.

Development of local capacities and infrastructure for the development of drugs and vaccines is expect-ed to improve health care both directly and indirect-ly. Technology transfer from developed countries to developing countries does take place, but perhaps the strategy should be re-evaluated to ensure that appropriate, complete and sustainable technology is transferred. The establishment by different organi-zations of clinical trial centres/networks in countries where the disease is endemic, as well as the creation of the European Developing Countries Clinical Trial Partnership (EDCTP), are excellent concepts geared towards the suggested direction. Indeed the estab-lishment of clinical trial sites in countries in which malaria is endemic is essential for phase II and III

Lead Lead Transitionidentification optimization

Earlydiscovery

Phase I Phase II Phase III

Dihydrofolatereductase(DHFR)

Syntheticperoxide(OZ)

Isoquine(superior 4-aminoquinoline)

Intravenousartesunate

Pyronaridineartesunate

Chlorproguanil-dapsone(LapDap™)Artesunate

Artemisone(semi-syntheticendoperoxide)

Fatty acidbiosynthesis(FASII)

Proteinfarnesyltransferase(Pf-PFT)

Falcipaininhibitors

PediatricCoartem®

4(1H)-Pyridones

Newdicationicmolecules

DB289

Fatty acidbiosynthesis(Fab I)

Noveltetracycline

Manzaminealkaloids

Entantiomers8-aminoquinolines

DHA

Piperaquine

Peptidedeformylaseinhibitor (PDF)

Glyceraldehyde-3-phosphatedehydrogenase

D I S C O V E R Y11 projects • 8 academic partners

5 pharmaceutical partners • 4 research institutes

D E V E L O P M E N T10 projects • 9 academic partners • 10 pharmaceutical partners

2 research institutes • 1 international organization

Figure 1. MMV product discovery and development portfolio, with a summary of key partners


studies, which assess the efficacy and safety of new drugs.

These efforts require an appropriate mechanism that encourages networking and share of available technologies in developing countries. This will help developing nations to learn from each other’s suc-cesses, as technical cooperation among the devel-oping countries could be an essential component of capacity building and technology transfer. As these efforts are put in place, it is equally important for developing nations to recognize that stable govern-ment and good management are essential ingredi-ents for sustainability.

6. CONCLUSIONS

Drug discovery and development require special-ized expertise and infrastructure, which are large-ly lacking in countries in which malaria is endemic. Several developing countries have the ability to reproduce finished products from imported raw materials, with limited chemical or therapeutic innovation. There is a need for facilities that comply with GLP and GMP, and several clinical study cen-tres need to be supported that can perform studies to good clinical practice (GCP) standard. Increased collaboration between developing and developed countries, and the development of local training courses will facilitate the introduction of such pro-cedures, but perhaps complete transfer of technol-ogy through regional centres (in disease-endemic countries) with some basic infrastructure and exper-tise should be considered. In turn, these centres will help to facilitate broader country-to-country train-ing, while participating in the global efforts to dis-cover and develop new drugs.

TDR, the Multilateral Initiative on Malaria (MIM), and organizations including the Wellcome Trust, the Bill and Melinda Gates Foundation etc. have made significant contributions to various aspects of research and development for tropical diseas-

es, including capacity building in endemic coun-tries. These efforts should be reinforced by the new public–private partnerships by means of contin-ued involvement of good scientists, institutions and companies in disease-endemic countries in their drug development efforts.

References

Medicines for Malaria Venture (2000). Draft business plan. Geneva.

Medicines for Malaria Venture (2001). Annual report. Geneva.

Global Partnership to Roll Back Malaria (2001). Antimalarial drug combination therapy. Report of a WHO technical consultation, 4–5 April, 2001. Geneva, World Health Organization (WHO/CDS/RBM/2001.35).

Ridley R (2002). Medical need, scientific opportunity and the drive for antimalarial drugs. Nature, 415:686–693.

Rosenthal P (2001). Antimalarial chemotherapy: mecha-nisms of action, resistance, and new directions in drug dis-covery. New Jersey, USA, Humana Press.

Lipinski et al. (1997). Experimental and computation-al approaches to estimate solubility in drug discov-ery and development settings. Advanced Drug Delivery Reviews, 23:3–25.

Olliaro P & Navaratnam V (2002). Technical cooperative network in developing countries for sustainable access for affordable, adapted medicines. The DND Working Group, Médecins Sans Frontières (www.neglecteddiseases.org).

Yuthavong Y (2001). Development and production of drugs for neglected diseases in endemic countries: A key to solving the medicines crises. The DND Working Group, Médecins Sans Frontières (www.neglecteddiseases.org).

Nwaka S and Ridley R (2003). Virtual drug discov-ery and development for neglected diseases through public-private partnerships. Nature Reviews Drug Discovery, 2:919–928.


Mal

aria

Annex 13 WORKING PAPER: Malaria vaccines


MALARIA VACCINES

Chetan E. ChitnisInternational Centre for Genetic Engineering and Biotechnology (ICGEB)New Delhi, India

1. THE NEED FOR MALARIA VACCINES

Malaria continues to be a major public health prob-lem in the tropical world. It is estimated that there are 300–500 million clinical cases of malaria each year worldwide; infection with P. vivax accounts for about 25% of these cases and infection with P. fal-ciparum primarily accounts for the rest. There are 1.4–2.7 million deaths attributable to malaria each year (Snow et al., 1999; Breman, 2001). Most of these deaths occur in African children and are caused by P. falciparum infections. The control of malaria has been difficult; efforts have been impeded by the spread of insecticide-resistant mosquito vectors and drug-resistant parasites. An effective malaria vac-cine could greatly assist efforts to control malaria and is urgently needed.

2. THE PARASITE LIFE CYCLE

Malaria parasites have a complex life cycle. Infection in humans is initiated when infected female anoph-eline mosquitoes inject sporozoites subcutaneously into the human host during a blood meal. The spo-rozoites enter the bloodstream and invade hepato-cytes within minutes of injection. Each sporozoite multiplies by schizogeny in the hepatocyte and dif-ferentiates into thousands of merozoites, which are released into the bloodstream, over a period of 5–15 days. In hepatocytes, P. vivax and P. ovale sporozo-ites can also develop into latent hypnozoites, which can lie dormant for months to years before differen-tiating into merozoites. Merozoites invade and mul-tiply in erythrocytes in the bloodstream to establish a blood-stage infection. At the blood stage, some of the parasites differentiate into gametocytes, which are picked up by mosquitoes during a blood meal. The gametocytes fertilize in the mosquito midgut and develop into sporozoites over a period of 10–22 days, thus completing the life cycle.

3. APPROACHES TO THE DEVELOPMENT OF MALARIA VACCINES

Malaria vaccines are being developed to target the parasite at different stages in its life cycle. This sec-tion briefly reviews some of the approaches being used.

3.1 Pre-erythrocytic stage vaccines

Immunization of human volunteers with irradiated P. falciparum sporozoites confers complete protection against sporozoite challenge (Rieckmann et al., 1979; Clyde, 1990; Hoffman et al., 2002). Analysis of the protective immune mechanisms elicited suggests an important role for cellular immune responses, pri-marily secretion of �-interferon (�-IFN) by CD8+ and CD4+ T cells (Good & Doolan, 1999). In animal models, high-titer antibody responses against spo-rozoite surface antigens have also been shown to provide protection by blocking hepatocyte invasion (Marussig et al., 1997). Vaccine strategies that tar-get the pre-erythrocytic stage thus try to elicit either cellular immune responses against infected hepa-tocytes or high-titer antibodies against sporozoite surface antigens. A partially successful pre-eryth-rocytic vaccine could play a role similar to that of other interventions, such as insecticide-treated bed-nets, and could have a major impact on public health in areas in which malaria is endemic.

3.2 Blood-stage vaccines

At the blood stage of the parasite life cycle, mero-zoites invade and multiply in erythrocytes, which do not have any antigen presentation. Vaccine strat-egies for the blood stage have therefore focused on eliciting antibody responses against either anti-gens on the merozoite surface, or parasite proteins expressed on the surface of infected erythrocytes. After repeated exposure to infection with P. falci-parum, adults residing in areas in which malaria is endemic acquire natural immunity to malaria (Day & Marsh, 1991). Passive transfer of immunoglobu-lins from such immune individuals to non-immune volunteers has been shown to control blood-stage parasitaemia, providing evidence for a role for humoral immune responses in naturally acquired immunity (Sabchareon et al., 1991). Studies in ani-mal models and in immune individuals residing in areas in which malaria is endemic have also impli-cated roles for antibody-dependent cellular inhibi-tion (ADCI), CD4+ T cells, nitric oxide and γδ T cells in blood-stage immunity (Druilhe & Perignon, 1994; Good & Doolan, 1999; Good, 2001). Since all the clinical symptoms of malaria are attributed to the blood stage of the parasite life cycle, vaccines tar-


geted against the blood stage of the parasite would reduce disease and could provide protection against severe malaria and death in areas in which malaria is endemic.

3.3 Transmission-blocking vaccines

Antibodies directed against antigens expressed on the sexual stages of the parasite can be picked up by the mosquito during a blood meal and can neutral-ize development of the sexual stages of the parasite in the mosquito, thus interrupting the parasite life cycle (Kaslow, 1993). Availability of assays carried out in vitro has allowed identification of candidate antigens that elicit transmission-blocking antibodies. Transmission-blocking vaccines will not protect vac-cinated individuals against infection or clinical dis-ease, but will prevent the transmission of malaria.

4. CANDIDATE MALARIA VACCINES UNDER DEVELOPMENT

4.1 Pre-erythrocytic stage vaccines under development

Efforts to develop vaccines targeted against pre-erythrocytic stages of the parasite have focused on sporozoite surface proteins, such as the circumspo-rozoite protein (CSP) and thrombospondin-related adhesive protein (TRAP), and on parasite proteins expressed in infected hepatocytes such as liver-stage antigens 1 and 3 (LSA-1 and LSA-3). Some of the leading candidates for pre-erythrocytic vaccines are discussed briefly below.

RTS,S

The vaccine RTS,S is a recombinant chimeric virus-like particle composed of wild-type hepatitis B virus surface antigen (HbSAg), and HbSAg fused to a fragment of P. falciparum CSP. RTS,S formulat-ed with the adjuvant AS02 has been shown to have a protective efficacy of 30–80% against artificial sporozoite challenge in adults. RTS,S also demon-strated 71% protective efficacy against natural infec-tion in semi-immune Gambian adults for the first nine weeks after immunization. Protective immu-nity waned rapidly thereafter (Stoute et al., 1997; Bojang et al., 2001; Kester et al., 2001). RTS,S is cur-rently being tested for protective efficacy in children in Mozambique.

CSP repeats in hepatitis B core protein particles

B and T cell epitopes from the P. falciparum CSP repeat region are expressed as a fusion with hepati-tis B core protein. The recombinant hepatitis B core protein particles are highly immunogenic and elicit high-titer antibodies against CSP in animal models

(Birkett et al., 2002). The safety and immunogenici-ty of CSP repeats in hepatitis B core particles formu-lated with alum are being evaluated in a phase I trial in healthy adults.

CSP peptides

Multiple antigenic peptides (MAP) based on CSP have been used for the induction of high-titer anti-bodies to P. falciparum sporozoites. A synthetic MAP vaccine containing minimal T and B cell epitopes from the P. falciparum CSP repeat region, was for-mulated with the adjuvants alum and QS21 and tested in phase I human trials. High-titer parasite-specific antibodies were elicited in human volun-teers (Kublin et al., 2002).

DNA, live vector

Prime/boost regimens using naked DNA plasmids, recombinant fowlpox virus (FPV) or modified vac-cinia virus (MVA) expressing multiple T cell epi-topes (ME) from P. falciparum antigens fused to P. falciparum TRAP have been used to elicit cellular immune responses against the pre-erythrocytic stage of the parasite (Schneider et al., 1999). Various regi-mens have been tested in phase I and phase IIa trials in adults to optimize immunization dose and sched-ule. Robust cellular immune responses are elicited and evidence for a quantitative reduction in liver-stage parasites upon challenge with artificial sporo-zoites has been observed in these trials.

Multiple-stage DNA vaccine

Multiple DNA plasmids designed to express P. falci-parum antigens from different stages have been test-ed in combination in phase I and phase IIa trials. Although DNA vaccines provide a convenient way to combine multiple antigens, and it has been dem-onstrated that immunization with DNA can elicit cellular immune responses in humans (Wang et al., 1998), this method of delivery requires optimization and may require boosting with recombinant FPV or MVA for optimal immune responses.

4.2 Blood-stage vaccines under development

Efforts to develop a vaccine that targets the blood stage of the malaria parasite have focused on par-asite proteins that are expressed either on the sur-face of merozoites or in apical organelles such as rhoptries and micronemes. These recombinant vac-cines primarily attempt to elicit antibody responses that will inhibit erythrocyte invasion and limit par-asite multiplication in the bloodstream. The leading blood-stage vaccine candidates are reviewed brief-ly below.


Merozoite surface protein-1 (MSP-1)

MSP-1, a protein (relative molecular mass, 195 000) expressed on the merozoite surface, is proteolytical-ly processed during invasion. Antibodies directed against MSP-119 (a C-terminal, conserved, cyste-ine-rich region of MSP-1; relative molecular mass, 19 000), which contains epidermal growth fac-tor (EGF)-like motifs, have been shown to inhibit invasion and provide protection in animal models (Good et al., (1998). Possession of antibodies direct-ed against MSP-119 also correlates with protection in endemic areas. Recombinant vaccines based on a C-terminal fragment, MSP-142 (relative molecular mass, 42 000), or on MSP-119 are being developed. Recombinant MSP-142, formulated in AS02, was shown to be immunogenic in non-immune adults. A phase I trial in Kenyan adults is underway and trials in children are planned.

Long synthetic peptides

Two long synthetic peptide vaccines based on B and T cell epitopes of P. falciparum MSP-3 or P. fal-ciparum glutamate rich protein (GLURP) are being developed. In phase I trials, both vaccines induced cytophilic antibodies that may lead to clearance of parasites by antibody-dependent cellular inhibition. Recombinant versions of these vaccines are also under development.

Erythrocyte-binding proteins

Parasite proteins that belong to the family of eryth-rocyte-binding proteins (EBP) include P. falciparum EBA-175 and P. vivax Duffy binding protein (PvDBP). The functional receptor-binding domains of both proteins lie in conserved, N-terminal, cysteine-rich domains referred to as PfF2 and PvRII respectively. Recombinant PfF2 and PvRII formulated in human-compatible adjuvants such as Montanide ISA720 and AS02 are immunogenic in animal models and elicit high-titer binding and invasion-inhibitory antibod-ies (Pandey et al., 2002; Singh et al., 2002). Phase I safety and immunogenicity trials with recombinant PfF2 and PvRII are planned.

Other blood-stage vaccines

Other blood-stage vaccines under development include those targeting merozoite surface proteins MSP-2, MSP-4 and MSP-5, and the apical merozoite antigen-1 (AMA-1). Immunization with these anti-gens in animal models has provided evidence for protective efficacy against blood-stage challenge. Methods for production of these recombinant vac-cines under current good manufacturing practice (cGMP) are being established for use in clinical trials.

4.3 Transmission-blocking vaccines under development

The leading transmission-blocking vaccine candi-dates under development are discussed below.

Pfs25, Pvs25

Antibodies directed against these antigens (relative molecular mass, 25 000) from P. falciparum and P. vivax have been shown to elicit antibodies that block the development of oocysts in mosquitoes (Kaslow, 1993). Both antigens contain conserved cysteine-rich EGF-like domains. Methods to produce correctly folded Pvs25 and Pfs25 under cGMP are established and phase I clinical trials with both antigens formu-lated with alum are planned.

Other transmission-blocking vaccines

Other transmission-blocking vaccine candidates include Pfs28, Pfs48/45 and Pfs230. Each of these antigens has been shown to elicit transmission-blocking antibodies. Methods to produce these recombinant antigens under cGMP are currently being established.

5. FUTURE DIRECTIONS IN MALARIA VACCINE DEVELOPMENT

Here we describe briefly the directions in which malaria vaccine development is likely to progress in the next 5 to 10 years.

5.1 Field trials of malaria vaccine candidates

Increased support for malaria vaccine development from a variety of public funding agencies and phil-anthropic foundations in recent years has made it possible to undertake clinical development of can-didate malaria vaccines. As described above, a num-ber of candidates will soon be tested in phase I and II trials. Typically, phase I trials to establish safety are first conducted in healthy adults in developed countries, where the majority of malaria vaccines are being developed. Next, phase I trials are conducted in semi-immune adults in areas in which malaria is endemic, followed by phase I trials in children in endemic areas. Phase IIa trials involving challenge by P. falciparum sporozoites may be used to estab-lish efficacy. However, such challenge trials may not always be feasible, especially in endemic area settings. Small-scale field trials (phase IIb) in semi-immune adults or non-immune children in endemic areas will provide the first indications of protective efficacy against natural challenge. Over the next five years, protective efficacy data from such trials should be available for candidate vaccines described here. On the basis of the protective efficacy data,


an iterative process may be required to improve efficacy, either by combining the most promising candidates or by improving variables such as for-mulation, dose and schedule of immunization. Once promising candidates with satisfactory efficacy are identified, phase III trials will be planned in endem-ic areas. A number of field trial sites have already been established in different regions of Africa and Papua New Guinea and should be available for field efficacy trials. Field trial sites are also being estab-lished in India (for vaccines targeting P. falciparum) and Colombia (for vaccines targeting P. vivax).

5.2 Combination vaccines

Data on protective efficacy from phase IIb trials will be used to identify promising vaccine candi-dates that provide some degree of protection. In the next phase, such vaccine candidates will be com-bined and the protective efficacy of the combina-tions will be tested. Targeting immune responses against multiple antigens from the same stage of the parasite, for example, multiple blood stage antigens, may provide synergistic effects and provide great-ly enhanced protective efficacy. Promising vaccine candidates from different stages may also be com-bined to target the parasite at different points in its life cycle. It would be extremely useful to combine a transmission-blocking vaccine candidate with either blood-stage or pre-erythrocytic vaccine candi-dates to reduce transmission in addition to prevent-ing infection and protecting against clinical malaria. The design of such vaccine trials, which attempt to provide protection as well as reduce transmission, will be complex. Finally, it will be necessary to com-bine vaccines designed to protect against malaria caused by P. falciparum and P. vivax, to address the needs of regions such as Papua New Guinea, south and south-east Asia, and Latin America, where both parasite species are endemic.

5.3 Delivery systems and adjuvants

The use of novel adjuvants and delivery systems may be necessary to elicit long-lasting protective immune responses with recombinant malaria vac-cines. For example, of three adjuvant formulations tested with RTS,S, only one, AS02, provided protec-tion in human trials (Stoute et al., 1997). These results highlight the need to develop appropriate presenta-tion and delivery methods to induce qualitatively and quantitatively appropriate immune responses. Immune responses to malaria vaccine candidates are also likely to be short-lived. It may be necessary to develop formulations such as slow-release parti-cles to elicit sustained immune responses.

5.4 Novel antigens

Efforts to develop vaccines against malaria have so far focused on a handful of antigens from the dif-ferent stages of the parasite. After the release of the complete P. falciparum genome sequence, it is now possible to undertake approaches using func-tional genomics to study the biology of the malar-ia parasite and its interaction with the host. These approaches are likely to identify novel antigens that may be promising candidates for malaria vaccines.

6. THE ROLE OF WHO/TDR IN GLOBAL EFFORTS TO DEVELOP MALARIA VACCINES

WHO/TDR has supported efforts to develop malar-ia vaccines for the past two decades. Here we list some points that might be considered as WHO/TDR re-evaluates its role in the context of global efforts to develop a vaccine against malaria.

6.1 Basic research

It is important to continue support for basic research on the biology of the malaria parasite, the patho-genesis of malaria, host–parasite interactions and immune responses to malaria. Such studies are like-ly to identify correlates of protective immunity as well as novel candidates for malaria vaccine devel-opment. WHO/TDR should continue to invest in basic research on malaria through investigator-ini-tiated grant proposals, and to encourage vaccine-related applications that arise out of such basic research.

6.2 Process development and clinical trials

Support for the clinical development of malaria vac-cines has increased significantly in recent years. As a result, a number of malaria vaccine candidates are under clinical development and are being tested in human clinical trials. The development of malaria vaccines will require an iterative process that will need sustained support. The clinical development stage of vaccine development requires significant resources. If WHO/TDR wishes to support the clin-ical development of malaria vaccine candidates, it will need to commit significant funds to this effort. Alternatively, WHO/TDR could form partner-ships with other funding agencies and offer to bear part of the costs of clinical development. In addi-tion, WHO/TDR could provide expertise on issues related to cGMP and current good clinical practice (cGCP) to assist researchers, especially those from developing countries, who are involved in the clini-cal development of malaria vaccines.


6.3 Regulatory affairs and ethics

Field trials of malaria vaccines will need to be car-ried out in areas in which malaria is endemic. Most countries in these areas have poor regulatory mech-anisms with which to oversee the development of novel vaccines. Given its unique position, WHO can play an important role in assisting these countries to establish satisfactory regulatory mechanisms and ethical review procedures to oversee trials of malar-ia vaccine candidates. Moreover, WHO/TDR can help with providing clinical monitors to ensure that trials of malaria vaccine candidates are performed in accordance with internationally acceptable cGCP standards.

6.4 Development of human resources in endemic areas

WHO/TDR should continue to play an important role in training and development of human resourc-es in endemic countries. The goal of the human resource development effort of WHO/TDR should be the establishment of capacity to work in areas such as malaria vaccine development in endem-ic countries. This will require not only appropriate training but also support for qualified researchers to establish research groups to work on malaria vac-cine development in endemic areas.

6.5 Partnership and coordination

The development of a successful malaria vaccine is a task that is beyond the capacity of any single funding agency. WHO/TDR should form close part-nerships with other funding agencies to ensure cooperation and coordination between agencies supporting development efforts. Given its unique position, especially with regard to developing coun-tries, WHO can continue to play an important role in global efforts to develop a malaria vaccine.

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Annex 14 WORKING PAPER: New advances in the development of insecticides


NEW ADVANCES IN THE DEVELOPMENT OF INSECTICIDES

Hilary RansonLiverpool School of Tropical MedicinePembroke Place, Liverpool,United Kingdom

1. BACKGROUND

Insecticides form an integral part of most nation-al malaria control programmes. In many countries, centrally organized indoor residual spraying (IRS) programmes have largely been superseded by the use of insecticide-treated bednets (ITNs), which is more amenable to implementation at the communi-ty level. The limited number of insecticides that are suitable for all types of indoor application and are also sufficiently fast-acting to be effective against mosquitoes is a major concern for malaria control programmes. Furthermore, pressure from environ-mentalists is likely to cause a reduction in the num-ber of insecticides available in the future as, although exemptions exist to protect the use of insecticides for public health, a reduction in those licensed for agri-cultural use may force manufacturers to cease pro-duction for economic reasons.

Mosquitoes are widely exposed to four classes of insecticides either directly, through targeted use in public health campaigns, or indirectly, through con-tamination of mosquito breeding grounds by run-off from agricultural use of insecticides. The majority of ITN programmes employ pyrethroid insecticides. Carbamates and organophosphates have been evalu-ated for use in the treatment of bednets and found to be effective in killing mosquitoes (Fanello et al., 1999, Guillet et al., 2001), but toxicity and odour issues need to be addressed before these compounds can be recommended for use in such close contact with humans. For economic and safety reasons, current IRS programmes generally employ the organochlo-rine insecticide dichloro-diphenyl-trichloroethane (DDT), although in the 1970s and 1980s the organo-phosphates malathion and fenitrothion and later the carbamate, bendiocarb, were widely used for indoor application. Today, these classes of insecticides are predominantly employed as larvicides for mosqui-to control.

Several novel classes of insecticide have been regis-tered for agricultural use in the past decade. These

include the nicotinic acetylcholine receptor agonists (e.g. imidacloprid), phenyl pyrazoles (e.g. fipronil), which target the GABA receptor, and pyrroles (e.g. chlorfeapyr), which act by uncoupling oxidative phosphorylation in mitochondria. Many of these, however, are ineffective or unsuitable for mosquito control. Insect growth regulators (e.g. methoprene), chitin synthesis inhibitors (e.g. benzoylphenylureas) and bacterial toxins such as Bacillus thruringiensis can be an effective means of controlling mosquito larvae. However, for insecticides to be successful-ly employed to help break the malaria transmission cycle, they must target the adult mosquitoes when they are seeking a blood meal.

2. RESISTANCE TO CURRENTLY USED INSECTICIDES

The spread of resistance to existing insecticides in Anopheles mosquitoes is jeopardizing current malar-ia control programmes and adding urgency to the quest for novel insecticides. Resistance to DDT con-tributed to the failure of the campaign to eradi-cate malaria in the 1970s (Bradley, 1998). Today, the resurgence of vector control efforts as part of the Roll Back Malaria initiative has led to an increase in the use of ITNs, and there are justifiable concerns that widespread resistance to pyrethroids may compro-mise this approach. Understanding the mechanisms that cause insecticide resistance is vital to improve resistance management strategies, thereby prolong-ing the effectiveness of existing control measures, but such knowledge is also valuable in the devel-opment of new insecticides, for several reasons. Firstly, it is important to know that existing resis-tance mechanisms will not compromise the efficacy of potential novel insecticides. This is of particular importance when two different classes of insecti-cide act on the same target. For example, the phenyl-pyrazole, fipronil, introduced in 1996, has the same target as the now largely obsolete cyclodiene insec-ticides. Resistance to cyclodienes is widespread and remarkably stable, even in the absence of selection pressure (ffrench Constant et al., 2000) and therefore the finding that dieldrin-insensitive gamma-ami-nobutyric acid (GABA) receptors are markedly less sensitive to fipronil is a strong argument against the use of this compound in many regions (Hosie et al., 1995). Secondly, a limited number of enzyme fami-lies are involved in the breakdown of xenobiotics in insects. Understanding the diversity of these enzyme families will assist in the prediction of detoxification pathways for future insecticides, potentially leading to improvements in their formulations, which may delay the onset of resistance. This knowledge will also help ensure an appropriate choice of chemical for resistance management strategies involving the


use of either mixtures or rotations of insecticides. Ensuring that the insecticides have different detox-ification pathways within the insect will delay the onset of resistance associated control failure. Finally, only by elucidating the molecular details of resis-tance can we potentially reverse the phenotype by designing specific synergists. The current state of our knowledge of existing resistance mechanisms in Anopheles is outlined below.

2.1 Mechanisms of resistance

Three families of proteins are largely responsible for the metabolism of insecticides: the cytochrome P450s, carboxylesterases and the glutathione trans-ferases. Although individual proteins within these families had been characterized and several genes encoding these proteins had been cloned from mos-quitoes, only after the first insect genome sequence was determined (Adams et al., 2000) was the full extent of these protein families revealed. A recent analysis of the Anopheles gambiae genome identi-fied 111 genes putatively encoding P450s, 51 carbo-xylesterases genes and 31 glutathione transferases (Ranson et al., 2002).

Glutathione transferases have been implicated in resistance to DDT in several Anopheles populations (e.g. Prapanthadara et al., 1993, 2000; Penilla et al., unpublished observation). Recently, a glutathione transferase responsible for resistance to DDT in one strain of A. gambiae has been elucidated (Ranson et al., 2001) but it is not yet known whether this same enzyme (or its ortholog) is involved in resistance to DDT in other strains of A. gambiae or in other Anopheles species. In other insects, glutathione trans-ferases have also been implicated in resistance to pyrethroids (Vontas et al., 2001) and to organophos-phates (Huang, 1998) and the ability of mosquito glutathione transferases to metabolize these insecti-cides needs evaluating.

The family of carboxylesterase proteins is extensive in insects and includes the target site of organophos-phate and carbamate insecticides, acetylcholines-terases, plus a number of enzymes implicated in the sequestration or detoxification of these insecti-cides. Insensitive acetylcholinesterase been report-ed in malaria vectors from Sri Lanka (Karunaratne et al., 2000), Mexico (Penilla et al unpublished obser-vation) and Africa (P. Moholoai, personal commu-nication). A. gambiae (and probably most mosquito species) contains two genes encoding acetylcholin-esterases, whereas Drosophila melanogaster contains a single acetylcholinesterase gene. Interestingly, orthologous acetylcholinesterase genes are not necessarily the target site of insecticides in differ-

ent insect species (Weill et al., 2002). Elevated activ-ities of various esterase enzymes are frequently associated with resistance to organophosphate, car-bamate and pyrethroid insecticides. Depending on the esterases involved, the resistance can be specific to a particular insecticide or can confer broad-spec-trum resistance to a number of different insecticides (Oakeshott et al., 1999). Elevated esterase activities have been associated with resistance to insecticides in several Anopheles populations, but more research is needed to determine the mechanisms involved.

The third major family of proteins associated with the detoxification of insecticides are the cytochrome P450s. This is a very diverse family in insects and only certain subfamilies of P450s have been impli-cated in the metabolism of insecticide (Feyereisen, 1999). Elevated P450 activity has been widely impli-cated in resistance to pyrethroids in many species, but the lack of sensitivity of biochemical assays designed to detect increases in P450s in individual insects and the paucity of knowledge of the role of individual P450 enzymes in insecticide metabolism have prevented an accurate assessment of the effect of this mechanism on the success of ITNs. Recently, elevated expression of a particular P450 gene has been associated with resistance to pyrethroids in A. gambiae from east Africa (Nikou et al., 2003), but this preliminary finding needs further verification. If substantiated, it will then be necessary to look at independent foci of insects with pyrethroid resis-tance to determine both how widespread this resis-tance mechanism is in Anopheles populations and also the pattern of cross-resistance it confers.

An additional resistance mechanism that isof major concern for current efforts to control malaria, is knockdown resistance or kdr. This resistance phe-notype is caused by a mutation in the voltage-gated sodium channel of the insect’s nervous system, the target site of both DDT and pyrethroid insecticides. This resistance mechanism has evolved at least twice in A. gambiae (Matinez-Torres et al., 1998, Ranson et al., 2000) and is now present at very high levels in certain regions of Africa. Kdr has also been detect-ed in A. sacharovi (Luleyap et al., 2002), A. albima-nus (P. Penilla unpublished data) and A. stephensi (Enayati et al., 2003). Once identified, the mutation can be detected by a simple method using the poly-merase chain reaction (PCR), enabling studies to be conducted on its frequency in field populations and effect on mosquito control by ITNs.


3. NEW INSECTICIDE FORMULATIONS TO REVERSE RESISTANCE TO CURRENT INSECTICIDES

The above discussion outlines the mechanisms that have been selected in Anopheles mosquitoes to reduce their susceptibility to insecticides. In most cases of control failure attributed to resistance to insecticide, one or more of these mechanisms can be implicat-ed. But how far are we from using this knowledge to actually reverse the resistance? Piperonyl butox-ide (PBO) has been used as a synergist to restore the efficacy of pyrethroids in many instances. PBO is widely believed to act as an inhibitor of cytochrome P450-mediated detoxification of insecticides, but has also been reported to inhibit esterases and may have insecticidal properties in its own right (Devine & Denholm, 1998). This broad-spectrum effect of PBO is of concern if the insecticide-plus-synergist com-bination is to be used in close contact with humans, as in the case of ITNs. PBO has been shown to have inhibitory effects on human P450s (Franklin, 1976). This toxicity is compounded by the high concentra-tions at which synergists are commonly incorporated into insecticide formulations (typically at 5–25-fold higher concentrations than the active ingredient), and hence PBO is unlikely to be approved for the treatment of nets. However, if the enzymes specifi-cally involved in the detoxification of insecticides in insects were determined and characterized, rational drug design principles could be employed to devel-op non-toxic insecticide synergists. Clearly, the use of synergists adds to the cost of an insecticide formu-lation. However, it takes a minimum of 10 years and a multi-million pound (sterling) budget to develop a new insecticide. A non-toxic resistance “blocker” that is shown to be insect-specific could potentially be marketed more rapidly and at a lower cost. This “add-on” technology could also be used to develop the idea of “smart-sprays” that might facilitate the introduction of small molecules for blocking para-site development in the insect.

4. NEW TARGETS FOR INSECTICIDES

The availability of the sequence of the A. gambiae genome (Holt et al., 2002), and the sequence of the D. melanogaster genome (Adams et al., 2000) will clearly accelerate the identification of new insecti-cide targets. As regulatory and metabolic pathways in these species are elucidated, key target molecules can be identified. Comparative genomics will pro-vide insights into the conservation of these path-ways in other non-insect species, enabling processes unique to insects to be selected, thus reducing the risk of human toxicity associated with blocking

these pathways. Several putative targets revealed by analysis of the genome have already been proposed, and some of these are discussed below. Firstly, how-ever, the reverse approach of designing novel com-pounds against previously validated targets will be briefly discussed.

Most existing chemical insecticides are nerve poi-sons. Their insecticidal properties are not disputed, but the environmental damage caused by the use of these chemicals has resulted in their use being restricted or even banned in many countries. If alternative chemicals could be developed that have the same biological target in the insect, yet do not exert an effect on non-insect species, novel targets would not need to be identified. This is presum-ing, of course, that environmental concerns, and not resistance, precluded the use of the original insec-ticides. Thus one approach to the search for novel insecticides is to express the target site in vitro and to screen a library of compounds to identify highly specific agonists to these targets.

A potentially rich source of insecticide targets can found within the three protein families that are more commonly associated with detoxification of insecti-cides. Large numbers of carboxylesterases, glutathi-one transferases and P450s play no apparent role in the detoxification of insecticides, but instead per-form key roles in endocrinology or cell signalling pathways. For example, the carboxylesterases have been extensively studied for their role in the detoxi-fication or binding of organophosphate insecticides, but a significant proportion of proteins in this family are not catalytically active. Several of these proteins, including neurotactins, neuroligins, gliotactins and glutactins, are involved in development and neu-rogenesis (Ranson et al., 2002). Understanding the function of these proteins may lead to the identifica-tion of novel targets.

Key regulatory pathways involved in arthropod endocrinology are the focus of much research. The cytochrome P450 family plays a vital role in many of the processes involved in these pathways. For example, several P450s that are vital to the syn-thesis of ecdysteroid hormones have been identi-fied (Kappler et al., 1988). In Aedes aegypti, an ovary ecdysteroidogenic hormone has been isolated that is released from mosquito brains after blood feed-ing and stimulates ovaries to begin secreting ecdys-teroids leading to egg yolk protein secretions by the fat body (Brown et al., 1998). The orthologous gene has recently been characterized in A. gambiae, but is absent from D. melanogaster, indicating that this pep-tide may be specific to blood-feeding insects (Riehel et al., 2002). Disrupting the ovary ecysteroidogen-


ic pathway, or other key regulatory pathways in insects, either by inhibiting the synthesis of these hormones, blocking their receptors or stimulating their degradation, could lead to novel methods of mosquito control.

An alternative approach to controlling diseases spread by blood-feeding insects is to break the trans-mission cycle by targeting host-seeking and/or feed-ing responses, so as to divert the insects from feeding on humans. Understanding the biological basis of anthropophily could lead to the development of a new generation of attractants and repellents. Insects rely on semiochemicals to interact with other insects and to locate food sources. Most semiochemicals are detected by chemosensory sensilla, often located on the insects’ antennae. Several odorant-binding pro-teins have been identified in mosquitoes (e.g. Vogt et al., 2002). These binding proteins then bind to G-protein coupled receptors that trigger the appropri-ate host response. A total of 276 G-protein coupled receptor proteins have been identified in the A. gam-biae genome, including 79 candidate odorant recep-tors (Hill et al., 2002). Elucidation of these signalling pathways could lead to exciting opportunities for reducing the vectorial capacity of mosquitoes.

5. RESEARCH PRIORITIES

There is clearly an urgent need for a new genera-tion of adulticides to help combat malaria. based Approaches based on functional genomics hold great promise for unravelling previously intractable biological processes in mosquitoes. Many of these will provide suitable targets for a new generation of highly targeted insecticides. Economic pressures will dictate the feasibility of this approach, but the following research priorities are recommended:– In the immediate future, every effort should be

made to prolong the effectiveness of pyrethroids for malaria control. This involves understanding the extent and effect of resistance on the use of these insecticides in current malaria control pro-grammes.

– Research into biological processes in mosquitoes is needed to characterize novel putative target sites for insecticides. Several potential pathways have been highlighted that warrant further research.

– Comparative genomics should be widely employed to assess the conservation of these targets and assess the likelihood of toxicity in mammals.

– Further studies on gene flow between malar-ia vector populations will improve the ability to manage current and future cases of resistance to insecticides.

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Bradley D (1998). The particular and the general. Issues of specificity and verticality in the history of malaria control. Parassitologia, 40:5–10.

Brown MR et al. (1998). Identification of a steroidog-enic neurohormone in female mosquitoes. The Journal of Biological Chemistry, 273:3967–3971.

Devine GJ & Denholm I (1998). An unconvention-al use of piperonyl butoxide for managing the cot-ton whitefly, Bemisia tabaci (Hemiptera: Aleyrodidae). Bulletin of Entomological Research, 88:601–610.

Enayati AA et al. (2003). Molecular evidence for a kdr-like pyrethroid resistance mechanism in the malar-ia vector mosquito Anopheles stephensi. Medical and Veterinary Entomology, 17:138–144.

Fanello C et al. (1999). The kdr pyrethroid resistance gene in Anopheles gambiae: tests of non-pyrethroid insecticides and a new detection method for the gene. Parassitologia, 41:323–326.

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Annex 15 WORKING PAPER: Sociocultural and behavioural issues in the treatment and prevention of malaria


SOCIOCULTURAL AND BEHAVIOURAL ISSUES IN THE TREATMENT AND PREVENTION OF MALARIA

Halima Abdullah Mwenesi Regional Research CoordinatorNetMark Africa Regional Malaria ProgramKyalami Business ParkMidrand, South Africa

1. SUMMARY

Sociocultural practices and social structure/organi-zation play a significant role in the treatment and prevention of malaria. This recognition has signif-icantly pushed the malaria agenda forward in the last decade, albeit at a pace that is still not satisfac-tory. With approximately half the world’s popula-tion living in developing countries lacking access to public health services, and the confirmation of the hypothesis that malaria is a disease of the poor, it has become critical that we should understand the social, cultural and behavioural issues relating to treatment and prevention of malaria. Specifically, it has become important to understand:– the processes underlying illness recognition;– treatment of fevers at the household and com-

munity levels;– pathways to treatment/care seeking, adherence

to treatment regimens;– malaria prevention/control within the ambit of

community participation/cooperation; and – mechanisms underlying behaviour change.

This paper describes the current status of research in this important area and highlights issues, oppor-tunities and challenges that still need our attention. Areas of research for the future are identified.

2. INTRODUCTION

Just over a decade ago, Oaks et al. (1) writing in Malaria: obstacles and opportunities. A report of the Committee for the Study of Malaria Prevention and Control: status review and alternative strategies urged that, “human behavior and social organization are vital determinants of the success of malaria control programs [but] … we do not know enough about how humans respond to malaria to be able to build strong multidisciplinary control programs”. About the same time another malariologist, Bradley (2) wrote, “when the insights of anthropology [human

behavior and social organization] and education fully permeate the way in which environmental control is implemented and are not just added on as after thoughts … then real progress can be made”.

Since these statements were made, we have made good progress in trying to understand the host in the host–vector–parasite triangle, but we have yet to use our current (limited) understanding of human behaviour and social organization to influence the current improved strategies and evidence-based interventions and to effect meaningful change in the fight against malaria.

Nevertheless, the momentum has increased and we believe that challenges in this area will be surmount-ed in the near future.

3. MANAGEMENT OF MALARIA

3.1 Recognition and perceptions of malaria-like illness

As with other illnesses, a significant percentage of malaria-like illness is first recognized and defined at home. A number of studies conducted in the last decade (3–12), especially on children aged less that 10 years (the subjects of the majority of stud-ies), have highlighted the fact that recognition/def-inition of malaria-like illness is based on a people’s belief system, as it relates to the etiology of illness. The belief system forms the basis of categoriza-tion of illnesses into serious, mild or mundane (3, 13), which in turn determines the promptness with which care is sought, withheld or even withdrawn; the type of care sought – home, traditional or mod-ern; and the social network that will be involved in decision-making for treatment seeking (3, 14–17). The same literature also suggests that people living in areas in which malaria is endemic recognize the symptoms of mild malaria, which they view as an everyday, therefore mundane, illness; however, in most cases, people do not recognize that malaria can develop in severity, as indicated by convulsions and severe anaemia (among other presentations), which are still viewed in many communities as being sepa-rate disease entities with no relationship to malaria.

Intervention in this area has taken the form of health education/promotion targeted at mothers and other people who care for children, as well as drug-sell-ers, traditional healers, traditional birth attendants and community health workers, this material being designed to equip them with knowledge on symp-toms that require prompt treatment, appropriate treatment and the need to refer (18–25).


The main achievement in this area has been the raising of awareness; most studies conducted after the mid 1990s report that many communities are aware of the causation, transmission and symptoms of malaria (26, 27), and, in a small way, improved knowledge is leading to some minimal behav-iour change, both in use of antimalarial drugs and in ownership of bednets (24, 26–27, 38). However, awareness and improvement in knowledge con-cerning the above-mentioned parameters have not yet been translated into actions that could reverse the upward trend in incidence of malaria in any sig-nificant way.

The main challenge is that fever, which can be caused by many other conditions, remains the best symp-tom by which malaria can be described; because malaria mimics other conditions, it is difficult to come up with a “gold standard” set of symptoms by which malaria can be recognized. Other challeng-es are in the area of monitoring and evaluation; this must be done in a manner that allows for the associ-ation of this type of intervention to observed behav-iour change the effect of this type of intervention on observed behaviour change to be measured and dependence on “free labour” in the name of com-munity participation.

3.2 Treatment-seeking behaviour for malaria–like illness

As a corollary to recognition and definition of malaria at the household level, treatment of malar-ia, in both mild and severe forms, also commenc-es at home and, for the most part, continues outside of the formal health-care sector. Treatment takes the form of self-medication with antimalarials and/or antipyretics (3, 16, 21, 24, 28– 30, 37). This behaviour is so widespread that it has been postulated that self-medication may account for over half of all anti-malarials consumed worldwide (31). The antimalar-ial drugs and antipyretics consumed are obtained from “left-overs” saved in the house from a previ-ous episode (especially when drugs are obtained from health-care facility), retail outlets and drug sellers, and are frequently used irrationally or inap-propriately (3–29).

The many reasons postulated for widespread self-medication revolve around inadequacies of health-care facilities and delivery of services, including accessibility of the health-care facilities, cost, wait-ing time, lack of drugs and social distance of health workers (3–29, 32–34). Nevertheless, people do seek care from formal facilities (public and private) and informal sources, such as traditional healers, the choice being dependent on various factors, includ-

ing cost, distance and socioeconomic status. It is important to note that these sources of drugs that are not part of formal health-care services are not seen as alternatives, but as first tiers of care (3, 19, 36, 36). When illness persists or causation is redefined, people seek care from health-care facilities – albeit late in the episode of illness, with all the attendant consequences (42).

The available literature repeatedly shows that moth-ers/caregivers often do act in response to symptoms as they present, thus interventions have been con-cerned with making antimalarials available closer to people and training cadres of community members to distribute them. The training of these community members, who come under various names – commu-nity health workers, community-based distributors (18, 22, 39), and the training of shop-keepers and sellers of patent medicines (19, 24) and mothers (20) seeks to equip the trainees with information on the importance of “correct” diagnosis, giving out, sell-ing or dispensing only complete doses, the need to refer, and when to refer. The training of shopkeep-ers especially is seen as a cornerstone for the scaling-up of prompt, appropriate treatment of malaria at the household/community level (41). It is becoming even more important with the advent of pre-pack-aged, age-specific dosages of malaria; these will not only facilitate prompt, correct treatment and acces-sibility, but will also hopefully address the major problems of self-medication and poor adherence to completion of treatment; the latter is critical for treat-ment for malaria, especially as it relates to issues of treatment failure and drug resistance.

There are numerous challenges in this area. Satisfactory and optimal ways of engaging commu-nities and of distributing pre-packaged drugs have yet to be identified. Examples of issues include vol-unteerism and incentives for community cadres, logistical processes to ensure the timeous delivery of drugs from central locations, handling of the drugs at the community cadre level, and supervision from the formal health-care sector.

4. PREVENTION AND CONTROL OF MALARIA

4.1 Chemoprophylaxis and intermittent presumptive therapy for malaria

There is a dearth of studies on sociocultural issues relating to chemoprophylaxis for malaria, as revealed by the lack of a single publication on this issue in the publication database for the Partnership for Social Science in Malaria Control. One comprehensive review of prevention (chemoprophylaxis) of malar-


ia in travellers does not mention a single study on sociocultural issues. Such issues may include lack of adherence to dosage and instructions on duration of treatment, and complacency when symptoms pres-ent. This is currently not one of the prevention inter-ventions encouraged in Africa, but it is a clarion call for the millions of people who travel to countries where malaria is endemic.

Prophylaxis for people living in countries where malaria is endemic is not highly promoted. However, it may be time to rethink this stand. A large num-ber of young children living in countries in which malaria is endemic, but where epidemiological con-ditions vary geographically are at constant risk of death when they travel from within the same coun-try. A top pediatric hospital in Kenya has reported a large increase in the number of cases of malar-ia in the hospital soon after school holidays in chil-dren travelling from Nairobi to the Lake basin and coastal areas that are hyper-endemic for malaria (the Administrator, Gertrude Garden Hospital, per-sonal communication). This is an area that requires addressing.

Current knowledge on malaria during pregnancy supports the use of directly observed intermittent presumptive therapy (IPT) with sulphadoxine/pyri-methamine (SP). For this approach to be effective, pregnant women must be informed and empow-ered to change popularly-held cultural beliefs on use of antenatal clinics, time during gestation at which first contact is made with an antenatal clinic and, most importantly, educated to understand that fever is not a normal condition of pregnancy and that some medication, even if bitter tasting, is safe and will not lead to spontaneous abortion (15).

The preliminary results of an ongoing study on atti-tudes to SP in Zambia indicate that the people sur-veyed believed that pregnant women should not be given SP because it can cause miscarriage, and also that breast-feeding mothers should not take SP because the nursing baby’s blood “is too thin” and the baby could die as a result (Dr Mike McDonald, personal communication).

The challenge is to increase knowledge of the pro-tective value of malaria chemoprophylaxis for preg-nant women and young “local” non-immunes in countries in which malaria is endemic. It is also nec-essary to keep looking for drug candidates that preg-nant women can take without fear of losing their pregnancies. Most drugs used for prophylaxis have very dramatic side-effects (43) and concerted efforts to promote these drugs and to educate people about their benefits and side-effects are required.

4.2 Vector control and environmental issues

Potential mosquito breeding sites, comprising small, temporary, freshwater pools (man-made or natural) that are exposed to sunlight, abound in countries in which malaria is endemic. More breeding sites are created by human manipulation of the environ-ment (44, 45), mostly for necessary endeavours such as opening up land for agriculture and settlement, building dams for power generation and irrigation. Local factors that have a direct impact on breeding sites include farming methods, house structure and rubbish disposal. Of these, intervention from com-munities could work at the level of improving house structures to decrease the number of mosquitoes entering (46, 47), and rubbish disposal. To address the other factors, integrated vector control on a large scale, use of chemical interventions and other per-sonal protection interventions are required. It has been noted that residual indoor spraying seems to be less acceptable to householders than other inter-ventions; the cooperation of the householders is nec-essary for success. There is no body of social science literature on integrated vector control and manage-ment; this is a good area for research.

One practice that was variously encouraged but was found to be ineffective over the years was clearing of bush and filling up of water pools around homes, which still finds a place of honour in many a malaria health education write-up. Although it was noted 55 years ago that bush clearing has no place in malaria vector control, the myth still persists (40).

4.3 Personal protection with insecticide-treated materials

It is an accepted fact that insecticide-treated materi-als (ITMs) – including nets and curtains – are effec-tive in reducing morbidity and mortality caused by malaria, as demonstrated specifically in controlled trials (48–51), in small projects (52) and under nor-mal field conditions (53). In this regard, promotion of ITMs in all countries in which malaria is endemic is a high priority. Questions about availability, acces-sibility, affordability and acceptability, and therefore appropriate use, continue to be addressed in both small projects and large-scale programmes; slowly but surely, coverage figures are rising.

Health education appears to be improving malar-ia-specific knowledge, which in turn is reportedly having some positive impact on net/ITN owner-ship at the household level (27). However, control programmes are still grappling with distribution, affordability and equity issues, whether they use social marketing or normal commercial approaches. The main challenge on the people side, other than


cost, is ensuring appropriate use by the most biolog-ically vulnerable people, pregnant women and chil-dren aged less than five years, and reaching those who are economically vulnerable, the “poor of the poor”. Parents continue to use the available net in a household, especially if it is the only one, and new information is that parents use the newest net/ITN and children use older nets that have probably been handed down (27). Also, there is still widespread use of this tool seasonally, i.e. only when mosquito densities are perceived to be high (26). At the distri-bution level, the major challenge faced by retailers and small-scale traders who would really be able to deliver nets and treatments out to remote plac-es is lack of credit, although the demand exists. This is another area that would benefit from research to determine, for example, whether nongovernmental organizations could address this problem.

Re-treatment remains another big challenge, even under the best of circumstances. Wide-scale produc-tion and availability of nets treated with long-last-ing insecticides should help this situation. However, communication (with regard to health education about how to re-treat nets etc.) has to continue for all the normal nets that will still be on the ground.

5. GENERAL CHALLENGES

Communication for behaviour and/or demand creation is critical for all the areas of intervention described in this discussion paper, but has not received enough attention. Most intervention pro-grammes include an information, education and communication component, and it is anticipated that this component is able to create demand and/or influence behaviour. However, in most of the lit-erature referred to in this paper, the approach to design of this component is neither systematic not well planned, and it is usually reduced to the pro-duction of posters and brochures, or geared towards specific instructions regarding, for example, dosage, duration of treatment, and how to treat and hang a net. The few small projects that have reported suc-cess in this area have yet to be tested and evaluated in large-scale settings.

This is an area that requires attention and adequate funding; to effect change in behaviour requires sustained long-term activities and not a few edu-cation projects before and after the launch of the programme, which mostly stop at raising aware-ness. With functional national malaria control pro-grammes and Roll Back Malaria secretariats now in place in many countries, those players with a role in malaria control within countries should be chal-lenged to work closely together, especially on com-

munication for behaviour change; their combined resources could thus be used to address key issues in a sustained way and key messages could be addressed in a generic manner to avoid confusing the public. This would stretch the resources avail-able for communication, and sustain this activity in a way that would, in this author’s opinion, increase the chances of effecting meaningful demand cre-ation and behaviour change.

Most importantly, as drugs/pre-packages, nets and re-treatment kits are commodities, it is important that those responsible for the communication com-ponents of interventions understand clearly that demand creation must first satisfy the “four Ps” of marketing – product, place, price and promotion. Promotion should only be carried out when the product is available in the right place and the right price.

The results of a few studies that have included gen-der as a variable when analysing uptake of malaria interventions and use of health-care facilities indi-cate that there are gender differentials in, for exam-ple, spending decisions, use of facilities and net/ITN ownership. Many more studies need to consider this variable in order to consolidate the current picture, which is currently hazy.

While it is desirable that communities should be involved in the development of activities and in health development in particular (54), some cau-tion should be used so that the partnership is not seen in an overly romantic light. The organizers of most interventions based in communities seem to assume that community members have suffered so much from malaria that they will volunteer their time free-of-charge to be trained, or to train others, to act as health educators, drug dispensers/ven-dors, ITN vendors/distributors, registrars of births and deaths, referral points and even specimen col-lectors.

However, literature on community participation from the late 1980s to the early 1990s, indicates that this area is fraught with very real problems (54); these problems should not be ignored in the bid to scale up malaria intervention programmes in order to create meaningful community participa-tion. It has to be remembered that these communi-ty-based workers invariably deal with various other disease programmes, which might treat the same “volunteers” differently. New research is required determine what expectations the community health worker of the 21st century have in respect of their participation in intervention programmes.


6. CONCLUSION

We have accumulated a body of knowledge con-cerning sociocultural and behavioural aspects of the treatment, prevention and control of malar-ia; this knowledge is and will continue to be crit-ical in informing efforts to scale up all available malaria interventions. It is important that the pro-cesses by which these interventions are implement-ed are carefully evaluated and documented, so that we are informed and ready to deal with sociocul-tural and behavioural issues that will be raised by future interventions, such as the long-awaited vac-cine against malaria.

Useful manuals and monographs that are excellent resources for programmes are also available. An inventory of these resources and wide dissemina-tion of the same should be undertaken in order to stop re-inventing the wheel (to avoid unnecessary duplication of efforts) and to open up other areas of research. We have to move beyond studies of knowl-edge, attitudes and practices/behaviour as stand-alone projects, and to put more effort in working within intervention programmes to answer opera-tional questions.

There is an immediate need for research into com-munication for behaviour change. Most other required research is of an operational nature or is in the realm of monitoring and evaluation; most ques-tions requiring attention are generated by activities/operations in interventions. Thus, for the moment, we still have many issues to address relating to scal-ing-up of useful interventions in case management, vector control, personal protection and malaria in difficult circumstances. Community-directed initia-tives have been shown to work for other tropical diseases, for example, onchocerciasis and filaria-sis. We should seek optimal ways to achieve simi-lar success, despite the complexity of malaria in all its aspects.

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Mal

aria

Annex 16 WORKING PAPER: Social, political, economic and inequity issues related to malaria resurgence and inequalities in access to treatment for and prevention of malaria


SOCIAL, POLITICAL, ECONOMIC AND INEQUITY ISSUES RELATED TO MALARIA RESURGENCE AND INEQUALITIES IN ACCESS TO TREATMENT FOR AND PREVENTION OF MALARIA*

H. K. HeggenhougenDepartment of International HealthBoston University School of Public HealthBoston, USA

1. INTRODUCTION

It is in the combination of the skills and methods of suc-cessive generations that good control of malaria emerg-es. W hen the insights of anthropology and education fully permeate the way in which environmental con-trol is implemented and are not just added on as after-thoughts, and when the most sophisticated results of molecular biology are applied through appropriate sim-ple technologies to epidemiological strategies developed decades ago, then real progress in control can be made. (Bradley, 1991: p. 28)

Malaria is a disease of poverty … Because ignorance, apathy, lack of means or access to medication often pre-vent them from seeking help early enough the most serious manifestations of tropical diseases are invari-ably seen among the underprivileged. (Reuben, 1993: p. 473)

The sociocultural environment is a significant fac-tor in the epidemiology of malaria. Indeed, the suc-cess of the Roll Back Malaria initiative depends on paying serious attention to social, political, econom-ic and equity issues. While the value of doing this is generally accepted within public health circles, it is only recently that this is receiving more than superficial attention. The interrelationship between infectious disease and behavioural and sociocultur-al factors needs to be re-emphasized and made a central part of malaria control strategies.

As Brown has noted:There has been little written about social factors in the modern resurgence of malaria. This is because the focus of public health, and malariology in particular, has been

narrowly fixed on the parasite and the mosquito vector. The bigger picture has been neglected – namely that increased rates of malaria morbidity, although direct-ly influenced by changes in the parasite and vector, are more directly caused by human behaviors. Those behaviors are both related to individual culturally coded patterns and larger-scale sociological phenomena including the political-economic level. (Brown, 1997: p. 130)

Human behaviour is related to risk of malaria, and a range of cultural and social factors, including differ-ent explanatory models about etiology and appro-priate preventive and treatment actions, influences such behaviour. A considerable gap remains between “correct scientific knowledge” and the accepted practices and beliefs about malaria held by dispa-rate groups of people, but that does not mean that these can or should be precipitously pushed aside by the provision of “correct” knowledge. We must recognize that “perceptions of illness, knowledge and understanding of illness are socially and cul-turally constructed, as are actions taken with regard to treatment” (Tanner & Vlassoff, 1998: p. 525), and that such perceptions cannot be changed overnight.

While this is true, malaria must also be seen as being linked with poverty; there is some debate, howev-er, as to the primary direction of this relationship. The position advanced here is that the growing gap between rich and poor, the increase in marginal-ization, and the swelling numbers of people living in absolute poverty are the major causes for con-cern, although we also recognize that morbidity and mortality caused by malaria may lead to poverty. It is clear that the health (including protection from malaria) of a burgeoning group of people will not improve unless poverty and expanding inequality are reduced. This is of course a huge task – often thought of as beyond the realm of any health ini-tiative – yet, although this is an enormous task, we must not for “practical reasons” lose sight of this interconnection. This is, of course, not to argue that malaria cannot be controlled before we have signif-icantly reduced poverty – that would be destruc-tive and inhibiting to valuable efforts on the part of Roll Back Malaria – but we must at least be aware of the link between poverty and malaria, recogniz-ing poverty as a risk factor for malaria and as an inhibiting factor for both preventive and curative malaria interventions. We must at least address the larger issues of poverty and inequality if we are to be taken seriously in our quest to tackle malaria. We

* Adapted from Ch. 1, Introduction: sociocultural and equity issues in malaria control, in: Heggenhougen HK, Hackethal V, & Vivek P, The behavioural and social aspects of malaria and its control – an introduction and annotated bibliography, 2003 (SEB/TDR/WHO).


must recognize that any malaria control effort may be limited if not cognizant of local social, economic, and political contexts, as well as cultural.

2. BEHAVIOUR AS A FACTOR IN HEALTH

Human behaviour – much of which is influenced by social, cultural, economic, and political factors – is clearly related to health, including risk of infectious diseases such as malaria. Whether it is intentional or not, human behaviour affects health-promoting and disease-preventing activities, in some instances increasing risk and in others reducing it. Although people’s behaviour may increase risk of malaria, and this deserves attention, to change such behav-iour is not easy. Indeed, there are many reasons why particular behaviours exist and they are often tied to considerable benefits in areas quite distinct from health. It is not usual that “these people don’t know any better,” but rather that their native logic and rationality make sense within the realities and limi-tations of their local circumstances.

While most attention is placed on understanding the behaviour of and significant sociocultural factors in communities of potential sufferers from malaria, it is also important to understand the sociocultural and behavioural characteristics of the health-care sys-tem itself, and the factors influencing the behaviour of health-care personnel. In research on malaria, rel-atively little attention has been turned toward the health-care system and the dominant attitudes of health-care personnel as factors influencing accept-ability and use of preventive and curative servic-es. Hongvivatana (1991: p. 72), for one, states that “What is critically needed is … behavioral analysis of the [malaria] control bureaucracies at various lev-els, just like studies of human behavior, values and belief systems, social structure and relations in the target population.”

3. EXPLANATORY MODELS OF DISEASES

One way to begin to understand the importance of sociocultural factors is to recognize the existence of different etiological explanatory models. Different explanatory models are prevalent throughout the world, in developed as well as in developing coun-tries. These are primarily formed by cultural and subcultural ethnomedical norms, but also by more specific factors, such as personal experiences of ill-ness or those of friends, relatives, and particular social groups. Most of these explanatory models vary, at least to some degree, from the biomedical

model, even in developed societies, and relate to prevalent local preventive and therapeutic actions.

Explanatory models are not only concerned with how an illness (malaria) occurred but also with why it occurred in a particular person at a partic-ular time. This attention to both the “how” and the “why” may not be a major problem to the malaria control effort if the “how” aspect does not conflict with conventional biomedical wisdom, and if preoc-cupation with the “why” aspect does not take pre-cedence in terms of locally-defined preventive and treatment action, thus delaying or inhibiting effec-tive therapy and prevention. Unfortunately, that is often the case. What presents even more of a prob-lem is when neither the single (how) nor the multi-ple (how/why) aspects of an explanatory model fit with a public health model. Cultures also create ill-ness labels as well as diagnostic categories. In differ-ent parts of the world, the signs and symptoms of malaria are given unique names, and these may not be associated with malaria at all. The result is that life-saving treatment is significantly and often fatal-ly delayed. This warrants the attention of any malar-ia control effort

Effective malaria control programmes need to be aware of these factors and to establish a public health alliance (including both a therapeutic and preven-tive union) with individuals and communities. While this may not immediately eliminate “false” notions, it may at least bridge the various explanato-ry models so that effective and timely treatment and preventive action can be taken.

4. CONSEQUENCES OF CONSIDERING SOCIOCULTURAL FACTORS AS AN AFTERTHOUGHT

“Only in retrospect has it become fully clear that the failure of malaria eradication was in large part a fail-ure at the social and organization levels” (Wessen, 1986: p. iii). Too often, behavioural and sociocultural factors are considered too late and involvement has been too peripheral. Of course, this does not mean that any and all involvement from the social scienc-es in malaria control has been or will be sufficient or productive. The research carried out to date has not been of uniformly high quality, but it is widely agreed that inattention to sociocultural factors was a major reason for the failure of earlier efforts to con-trol malaria. The current interdisciplinary approach to malaria control (as reflected by this meeting) sug-gests that Etkin’s admonition is much less true now than when she voiced it in 1991, yet it is one we still cannot ignore:


To the extent that contemporary malaria control pro-grams deviate little from their early design, and that too many studies still conclude that sociocultural vari-ables should have been taken into account at the pro-gram’s onset, the redundancy in recommendations for program design is apparently necessary … Because failure to deal even relatively superficially with the behavioral dimension squanders the technical sophisti-cation and competence of mosquito control technology and the prophylaxis and chemotherapy of plasmodial infections. (Etkin, 1991:59)

5. THE LIMITATIONS OF HEALTH EDUCATION IN MALARIA CONTROL

Twenty years ago, Gramiccia (1981) noted four main reasons for the failure of health education in malar-ia control:– The type of populations that suffer from endem-

ic malaria (accessibility is often difficult, and the medical facilities available to them are scarce);

– Malaria is part of a socioeconomic depression complex from which people have difficulty sin-gling out malaria for particular concern (why malaria rather than poverty, hunger, or other diseases or conditions?);

– The nature of the disease itself, specifically the complexity of its epidemiology;

– The health education methods currently employed (generally speaking, they have not been well adapted to local situations).

While most malaria health education efforts may not now be failures, they still face the same difficulties referred to by Gramiccia. And while we can clearly link behaviour with risk of malaria, such behaviour will not necessarily be changed by infusion of “cor-rect knowledge”. We should heed Farmer’s (1999) caution not to exaggerate people’s agency, or power, to effect beneficial changes for their own health and welfare.

We return to the need not only to single out the prob-lem of malaria, but also to attack it as yet another aspect of a much wider effort to intervene in improv-ing people’s lives. Of greater importance to many people is “subsistence anxiety,” that is, concerns over security, employment, availability and pro-ductivity of land, and thus the accessibility of food. Behaviours that may pose a high risk for malaria, but are integrated with a sociocultural system and driven by expectation of economic gain, may have both economic and social benefits and may be dif-ficult to change, despite the possession of appro-priate knowledge about the risk factors for malaria. As Brown puts it, “the continuation of brutal pover-ty and hunger in much of the world is undoubtedly

linked to large numbers of unnecessary deaths from malaria” (Brown, 1997: p. 122).

Although there is some recognition of malaria as a disease of poverty, solutions are seldom multi-pronged intervention against both malaria and pov-erty. Malaria may be perceived as a relatively minor malady in the hierarchy of problems with which people have to deal every day. This underscores the need for understanding not only people’s percep-tions and some of their cultural associations, but also the whole context of their lives that give shape to these perceptions and behaviours. Attention must be paid to local realities (including, but not only, cul-tural characteristics) as they shape ideas and behav-iour. Experiences that influence perceptions range from economic deprivation, to the spread of diseas-es considered more life-threatening than malaria, to war and social conflict. Moreover, perceptions may vary within a cultural entity, shaped by such fac-tors as educational level, social status, and degree of exposure to an urban or cosmopolitan environment. All these factors should be, but are often not, consid-ered when formulating and implementing a malaria education campaign.

While health education is important and should cer-tainly be a main activity of the anti-malaria initia-tive, imparting knowledge is not enough. Even with “correct” knowledge, people may not necessarily act in a way which to public health professionals seem in the target population’s own best self-inter-est. We must be aware that our view may be too focused and too limited, and that a number of other factors influence behaviour. To mount an effective and appropriate initiative we need to gain answers to the “why” questions of people’s behaviour. For this, qualitative research methods (often in concert with quantitative studies) are the most appropriate. People’s behaviour and reasoned actions are integral to sociocultural norms and a striving for econom-ic benefit in often very difficult circumstances, and must be understood before any behaviour change initiative is formulated and promoted.

6. SOCIOECONOMIC FACTORS AND RISK

Any review of relevant factors to be considered for worldwide control of malaria must give specific attention to the link between socioeconomic inequi-ty and disease epidemiology. The scientific evidence for this is both overwhelming and accumulating.

In malarious regions, it can be argued that the reduction and control of the disease is a prereq-uisite for economic development. While evidence


has been gathered to show that development is a consequence of good health, the indications to the contrary, namely, that improved health is a result of (social) development, appear more convincing. Specifically related to malaria, there are those, such as Brown (1986), who argue that the proposition that “malaria blocks development” (implying that con-trol of malaria would foster development) cannot be substantiated. Using the cases of Sardinia and Sri Lanka, Brown has shown that a drastic reduction in the incidence of malaria did not result in increased social or economic development, as expected.

While we believe that development is primary, we certainly do recognize that the reduction of the inci-dence of malaria is a social good in and of itself, and thus one element of an overall process of social development. But while we argue for a focused attack on malaria, we cannot avoid noting that, without attention to more overarching issues and recognizing that an attack on malaria must function within a certain context, where inequity and mar-ginalization are often prominent, any improvement in health, including malaria, may be short-lived (see also Farmer, 1999).

Although we argue that (social) development must go hand in hand with malaria control, we can find ample evidence of many large development proj-ects that have done little in terms of social, or eco-nomic, development for the poor (Kim et al., 2000). In fact, there is substantial evidence that a number of development projects, and large-scale economic enterprises in general, have damaged the welfare of already disenfranchised groups and have increased, rather than reduced, the risk of malaria for poor people (Silva, 1997; United Nations Development Programme, 1999). Dam construction, extensive irri-gation schemes, widespread agricultural use of pes-ticide, and the (permanent and cyclical) migration of large population groups in search of income as migrant labourers or as colonizers (e.g. in Brazil) of forest areas are only a few of the “development” activities that have been negatively associated with malaria (Gruenbaum, 1983; Santos, 1983; Packard, 1986, 1997; Coimbra, 1988; Oaks et al., 1991; Dinham, 1993; Brown & Whitaker, 1994).

Human behaviour, in the form of human settlement, mobility patterns, agricultural practices, and defor-estation, continues to be a factor affecting the prev-alence of malaria. We concur with Packard & Brown that:

“Ignoring the social and economic determinants of malaria allows people in International Health to con-centrate on mosquitoes and not to be concerned with thorny problems of poverty and inequalities in the dis-

tribution of land and capital resources … the social and economic benefits of malaria control continued to serve the needs of capital and the state, with only limit-ed advantages for impoverished rural farmers or urban slum dwellers … malaria control activities throughout the world may have created opportunities for exploit-ing new land resources, yet this did not necessarily produce ‘development’ in the sense of improved living standards of the majority of people inhabiting tropical regions of the world” (Packard & Brown, 1997: pp. 187–188; see also, Kim et al., 2000; World Bank, 1993).

Success of interventions will depend on sensitivi-ty to local specificities and variations. We think it is unrealistic to give a formula for an approach that will bring success to the worldwide malaria control initiative in all instances. Yet we strongly urge that people’s total sociocultural and economic circum-stances, their behaviours, and the reasons for them, must be studied and made known. The success of initiatives to control malaria depends on the incor-poration of such knowledge.

References

Bradley D (1991). Malaria – when and whither. In: Targett GAT, ed. Malaria: waiting for the vaccine. New York, John Wiley & Sons, p. 28.

Brown PJ (1986). Socio-economic and demograph-ic effects of malaria eradication: a comparison of Sri Lanka and Sardinia. Social Science & Medicine, 22:847–859.

Brown PJ (1997). Culture and the global resurgence of malaria. In: Inhorn MC, Brown PJ, eds. The anthro-pology of infectious disease: international health perspec-tives, 2nd ed. Amsterdam, Gordon and Breach Science Publishers, pp.119–141.

Brown PJ & Whitaker ED (1994). Health implications of modern agricultural transformation and pellagra in Italy. Human Organization, 53:346–351.

Coimbra CEA (1988). Human factors in the epide-miology of malaria in the Brazilian Amazon. Human Organization, 47:254–260.

Dinham B (1993). The pesticide hazard: a global health and environmental audit. London, Zed Books.

Etkin NL (1991). The behavioral dimensions of malaria control – guidelines for culturally sensitive and microecological germane policies. In: Malaria and development in Africa – a cross-sectoral approach. Washington DC, AAAS & USAID, pp. 59–69.

Farmer P (1999). Infections and inequalities: the modern plagues. Berkeley, University of California Press.


Gramiccia G (1981). Health education in malaria con-trol – why has it failed? World Health Forum, 2:385–393.

Gruenbaum E (1983). Struggling with the mosquito: malaria policy and agricultural development in the Sudan. Medical Anthropology, 7:51–62.

Hongvivatana T (1991). Human behavior and malaria. In: Sornmani S, Fungladda,W, eds. Social and economic aspects of malaria control, Bangkok, Thailand, Faculty of Tropical Medicine, Mahidol University, pp. 70–83.

Kim JY et al., eds. (2000). Dying for growth – global inequality and the health of the poor. Monroe, Maine, Common Courage Press.

Oaks SC et al. (1991). Social and behavioral aspects of malaria. In: Oaks SC et al., eds. Malaria: obstacles and opportunities. Washington DC, National Academy Press, pp. 257–277.

Packard RM (1986). Agricultural development, migrant labor and the resurgence of malaria in Swaziland. Social Science & Medicine, 22:861–867.

Packard RM (1997). Malaria dreams: post-war visions of health and development in the Third World. Medical Anthropology, 17:279–296.

Packard RM & Brown PJ (1997). Rethinking health, development, and malaria: historicizing a cultural model in international health. Medical Anthropology, 17:181–194.

Reuben R (1993). Women and malaria – special risks and appropriate control strategy. Social Science & Medicine, 37:473–480.

Santos SEB (1983). Mobility, genetic markers, sus-ceptibility to malaria and race admixture in Manaus, Brazil. Journal of Human Evolution, 12:373–381.

Silva KT (1997). “Public health” for whose benefit? Multiple discourses on malaria in Sri Lanka. Medical Anthropology, 17:195–214.

Tanner M & Vlassoff C (1998). Treatment-seeking behaviour for malaria: a typology based on endemici-ty and gender. Social Science & Medicine, 46:523–532.

United Nations Development Programme (1999). The human development report. New York, Oxford University Press.

Wessen AF (1986). Introduction: resurgent malaria and the social sciences. Social Science & Medicine, 22: iii-iv.

World Bank (1993). Investing in health – world develop-ment report 1993. New York, Oxford University Press.


Mal

aria

Annex 17 WORKING PAPER: The economics of malaria and its control


THE ECONOMICS OF MALARIA AND ITS CONTROL

Catherine Goodman, Kara Hanson, Anne Mills, Virginia Wiseman, and Eve WorrallHealth Economics and Financing ProgrammeLondon School of Hygiene and Tropical MedicineKeppel Street, London United Kingdom

1. INTRODUCTION

Since a review of the economics of malaria conduct-ed in the early 1990s (Mills, 1991), there has been some growth in the literature, although still very lit-tle relative to the need for understanding of the eco-nomic aspects of malaria and its control. The aim of this paper is to provide a brief review of current knowledge on economics of malaria, and to identi-fy key knowledge and research capacity needs. The paper is structured according to the main categories of economic analysis, namely:– Socioeconomic determinants of malaria trans-

mission;– Resource costs of malaria;– Characteristics of demand for prevention and

treatment of malaria;– Characteristics of supply of prevention and

treatment of malaria;– Economic evaluation;– Evaluation at the whole system level.

2. SOCIOECONOMIC DETERMINANTS OF MALARIA TRANSMISSION1

Malaria is frequently referred to as a disease of the poor. At a macro level, there is clear evidence that the burden of malaria is greatest among the poor-est countries of the world, especially those in sub-Saharan Africa. At a micro level, a recent review has shown that evidence on the distribution of malaria and incidence of malaria in poor and less-poor pop-ulation groups is mixed and contradictory (Worrall et al., 2003). Most studies using assets as a proxy for socioeconomic status (SES) have failed to establish a clear relationship between asset ownership and the incidence of febrile episodes (as a proxy for malar-ia). The most extensive study (Filmer, 2001), using

Demographic Health Survey (DHS) data, found no difference at the household level in incidence of fever between the poor and less-poor, but significant differences were seen at more aggregate levels2.

Evidence concerning malaria incidence and occu-pation is also mixed, although stronger than that obtained from asset-based indicators of SES. Unemployment and migration of labourers for agri-cultural work have been shown to be risk factors for malaria infection. Similarly, although the work done is limited, aggregate-level data suggest that ethnic group might be significantly related to the incidence of malaria.

Where studies have found differences in incidence of malaria by various socioeconomic proxies, these differences often did not survive multivariate sta-tistical analysis. Lack of clear findings is likely to be at least partly due to flawed methodologies and the inherent difficulties involved in measuring SES in developing countries. Furthermore, although there is a great deal of literature on equity and health more generally, limited research has been undertaken that looks at these relationships specifically for malaria. Where studies contain variables that allow the rela-tionship between SES and malaria to be investigat-ed, this was rarely the main topic of the research, a factor that helps to explain the weaknesses in the measurement of SES.

Nonetheless, the lack of consistent socioeconom-ic differentials regarding malaria incidence is not necessarily unexpected, given the epidemiology of malaria transmission, particularly its environmental aspects, and may be testament to the high degree of exposure to the mosquito vector regardless of SES, particularly in areas and periods of high transmis-sion. Susceptibility to malaria should, however, be distinguished from impact of malaria by socioeco-nomic group – this is considered in the next section.

Recommendations for future research:

1. A common methodology for measuring SES and poverty (including broader quantitative and qualitative aspects of poverty) is needed to develop a consistent body of evidence on the relationship between incidence of malaria and poverty, especially at the household and com-munity level.

2. Existing datasets (e.g. DHS data) could be re-analysed to provide further evidence on this relationship, at relatively low cost.

1 This section is based on Worrall, Basu & Hanson, 2003; readers should refer to this paper for detailed references.2 These findings have been questioned by malaria epidemiologists, as differences in transmission patterns across the large number of countries examined may confound the consistency of the SES–incidence relationship, or lack thereof (L. Barat, 2002, personal communication).


Further exploration is required on vulnerability to malaria by socioeconomic group in different set-tings.

3. ECONOMIC BURDEN 3

Information on the economic burden of malaria can help to target interventions efficiently and equita-bly, and to justify investment in research and con-trol. Such data can inform our understanding of the financial and time burdens of illness episodes, the determinants of treatment-seeking behaviour, and the differential economic impact on population sub-groups. Studies are conventionally categorized as macroeconomic or microeconomic studies.

Macroeconomic studies are concerned with impact at the level of the whole economy. Apart from Barlow’s seminal work published in 1967 (Barlow, 1967), this area of research has been neglected until very recently, when two studies have used malaria as an explanatory variable in economic growth models using cross-country regression analysis, and have demonstrated a significant relationship between growth in gross domestic product (GDP) per capi-ta and the burden of malaria (Gallup & Sachs 2001; McCarthy et al., 1999)

Microeconomic studies are concerned with impact at the level of a productive unit, such as the household or firm. A common method of estimation employed in many studies has been to sum the direct costs of expenditure on prevention and treatment, and the indirect costs of productive labour time lost. Evidence on direct costs suggests that households can spend quite substantial sums on prevention and especially treatment, and also that direct costs to governments are substantial. However the overall evidence on the microeconomic impact of malaria is patchy and weak (Sachs & Malaney 2002; Chima et al., 2003), and there are many problems in using such data to reflect the burden to society or the poten-tial benefits from control. Studies have generally focused on febrile illness, overestimating the burden of uncomplicated malaria, but underestimating the costs of severe illness, other debilitating manifesta-tions (especially neurological sequelae, anaemia and cognitive development), and mortality. Many stud-ies use inadequate data to calculate indirect costs, failing to account for seasonal variations, the dif-ference between the average and marginal prod-uct of labour, and the ways households and firms “cope” in response to illness episodes. An alterna-tive approach has been to estimate the net impact

on output by looking directly at the statistical asso-ciation between malaria and agricultural output through a production function. Again, findings have been contradictory, at least in part because of weak-nesses in data and methodology.

The evidence on the extent to which the burden falls more heavily on lower socioeconomic groups is rea-sonably consistent (Worrall et al., 2003). Studies examining SES using assets, education, and occupa-tion all yield data that suggest an inverse relation-ship between the impact of malaria and SES. There exists some evidence that in the case of agricultur-al labourers, the relationship between occupation and incidence is dampened – if not reversed – by the generation of community-level wealth (Worrall et al., 2003). This evidence, taken with that from Filmer (Filmer, 2001), implies that community-level data might provide a stronger indication of the link between malaria and poverty than does household data.

Indeed, a key problem with all microeconomic stud-ies is their inherent failure to capture the impact of coping strategies in response to the risk of disease, as opposed to the experience of actual illness. The impact of these anticipatory coping strategies (e.g. fertility decisions, choice of crop, investment deci-sions) cannot be captured by comparing households or firms exposed to the same degree of risk because they reduce the average productivity of all house-holds and firms, not just those experiencing illness during the study period. The contrast between the major impact of malaria found by macroeconom-ic studies and the weak evidence from microeco-nomic studies reinforces concerns on the value of past microeconomic work, and further highlights the need to develop a detailed understanding of the mechanisms by which malaria affects households and economies.


1. The scope of morbidity and mortality out-comes included in the disease burden need to be expanded, especially to include neurological sequelae and cognitive development.

2. Studies of microeconomic impact must be root-ed in a sound understanding of the nature of economic activities in the specific setting, and must confront the possible pervasive effect of malaria on the productive environment and the production possibilities and incentives of house-holds and firms.

3. A systematic approach to geographical variation

3 This section draws extensively on Chima et al., 2003.


is urgently required. Both economic and epidemi-ological factors vary greatly in different settings across Africa, but the haphazard set of country data available is of little use in making general-izations that are of value to policy-makers.

4. Studies are especially required on the impact of malaria on economic sectors, such as min-ing and quarrying, manufacturing, building and construction, commercial large-scale agriculture, tourism, and general commercial services.

5. Studies must be designed in order to inform policy action and not just to document total bur-den. This requires:– greater attention to economic burden by

socioeconomic group, and especially impact on the poorest; and

– emphasis on documenting the benefits of control and not just the costs of lack of con-trol, and identifying interventions which that would make the largest contribution to reducing the economic burden.

4. CHARACTERISTICS OF DEMAND FOR MALARIA PREVENTION AND TREATMENT OF MALARIA

The main purpose of most demand for health-care studies has been to understand the influences on household demand in order to predict likely trends and the impact of policy change. In a developing-country context, particular attention has been paid to the price elasticity of demand for curative care and, in turn, to the likely impact of user fees on use (Akin et al. 1981; Heller 1982; Akin et al. 1986; de Bartolome & Vosti, 1995; Asenso Okyere et al., 1997a).

Few studies have been attempted that estimate the relative influence of the various determinants of treatment-seeking for malaria and febrile illness (de Bartolome & Vosti 1995; Asenso-Okyere et al., 1997b; Mensah, 2000; Cropper et al., 2001). Those in the area of malaria have tended to focus on explain-ing patients’ choice of “provider” or “outlet”. For example, Asenso Okyere et al. (1997b) found that the choice of provider of malaria care is influenced by facility price, travel time, waiting time for treat-ment, a range of demographic factors (including education, age and sex) and, finally, the quality of care measured in terms of drug availability. They also reported that as income rises, individuals lean more towards self-medication when they get malar-ia. Bartolome and Vosti (1995) found that private treatment was highly price-sensitive and, to a lesser extent, wealth-sensitive. Their results also stress the importance of transportation costs – that these may deter rural individuals from buying private treat-

ment. Mensah (2000) found that a patient’s age, total expenditure, ethnicity, treatment costs and partici-pation in a local credit scheme significantly affected the choice of treatment.

Households must also make choices between dif-ferent types of product, the quantity of product and the timing of treatment. Relatively little is known about these determinants in the context of malaria. One exception is a recent econometric study of the demand for a malaria vaccine (Cropper et al., 2001). Cropper et al. report that the number of (hypothet-ical) vaccines that a respondent agrees to purchase was shown to increase with income, education, sus-ceptibility to the disease and being married. In con-trast, demand was shown to decrease with price, age of respondent and higher altitude. Holding household size constant, the demand for a vaccine was also shown to be lower the larger the number of children in the household.

The determinants of the demand for treatment for malaria are evidently varied. Other factors report-ed to influence demand include the incidence of malaria in the area, family members’ susceptibili-ties to malaria, household size, the perceived qual-ity of care/service, current health status and travel and treatment time (de Bartolome & Vosti, 1995; Cropper et al., 2001). To date, few attempts have been made to explore the way nationality, ethnici-ty, religion and tribal affiliation influence demand. “Regional” dummy variables are typically used as a proxy for these cultural differences (Dor & van der Gaag, 1993).

Finally, a particular concern recently has been demand and use of services by the poorest popu-lation groups. Studies consistently find socioeco-nomic gradients in ownership of insecticide-treated nets (ITNs), indicating that the poor have less access (Abdulla et al., 2001; Hanson & Worrall, 2002; Kikumbih et al, 2003; Onwujekwe, Hanson & Fox-Rushby 2004; Wardlaw, 2003). There is also evi-dence that those of lower SES are more vulnerable to the consequences of malaria infection, possibly as a result of less access to effective treatment once infected. Evidence on use of treatment shows that the poor seek different, possibly inferior, types of care than the less-poor. Moreover, there is evidence that antenatal clinics in Africa are under-used by the poor and therefore there are likely to be socio-economic inequalities in access to intermittent treat-ment/malaria prophylaxis during pregnancy.

Recommendations for future research:1. Econometric analyses of large-scale household

surveys are required to predict the effect of eco-


nomic, social and cultural factors on different health-care choices and to measure the respon-siveness of demand to these determinants.

2. Combined quantitative and qualitative studies should investigate: (i) the type of malaria-relat-ed health care that households would choose to purchase but fail to for lack of income/access/availability; and (ii) the changes that would make public sources of treatment more attrac-tive to patients and their families, and especially to the poorest.

3. Evaluations should be done of interventions designed to increase demand for appropriate prevention and treatment, especially amongst poorer groups, and to increase adherence to treatment.

4. Evaluation of interventions to increase adher-ence to treatment are required.

5. CHARACTERISTICS OF SUPPLY OF PREVENTION AND TREATMENT FOR MALARIA 4

In the last 10 years, considerable knowledge has been gained about the supply of malaria control (Hanson et al., 2004). There is abundant evidence that in many places, public health services are of poor quality, with long waiting times, inaccurate diagnosis, inappropriate prescription and advice, frequent occasions when drug stocks run out, and continued use of ineffective drugs. Patients often resort to the unregulated private commercial sec-tor where treatment may be inappropriate, although access costs may be lower. Inefficiency in public ser-vice delivery is also a problem: staff productivity is often low, especially when drugs are unavailable; polypharmacy raises drug costs unnecessarily; and excessive use of injectables increases costs. It is gen-erally believed that church service providers are more efficient than government providers, but evi-dence is patchy. Evidence is even more scarce on the efficiency of the private commercial sector.

With respect to prevention, there is patchy and much disputed evidence on the relative perfor-mance of public and private sectors in distributing ITNs, and such performance is likely to vary con-siderably across contexts depending on, inter alia, the capacity and accessibility of the public sector and the existence and degree of competitiveness of the commercial sector. Most ITN delivery strategies have been implemented on a very small scale, pro-

viding little basis on which to infer the costs and likely performance of a substantially scaled-up intervention. Furthermore, achieving the Abuja tar-gets of 60% coverage of children aged less than five years is likely to require a number of complementa-ry interventions involving public and private dis-tribution systems. Relatively little is known about the interactions among different distribution modes, and how they can be designed to encourage syner-gies and discourage negative interactions, such as crowding-out of commercial players.

The behaviour of providers is likely to be influ-enced by their knowledge, financial incentives, competition, perceptions of patient preferences, and any legal or regulatory sanctions for inappropri-ate behaviour, though studies in this area are very scarce. Many of the problems of service provision are linked to broader problems of health servic-es, including inadequate resources for public sec-tor services, poorly trained staff, and inappropriate incentives for health workers in both public and pri-vate sectors. Indeed, as Integrated Management of Childhood Illness (IMCI) is increasingly introduced, improving treatment for malaria must be addressed as a “horizontal” issue, along with improving other treatment services. However, there is little good evi-dence on how current problems can be addressed (Oliveira-Cruz et al., 2003)


1. There should be more analyses of relative per-formance (in terms of quality, equitable access, efficiency) of different types of service provider.

2. Evaluations of equity, efficiency, coverage and sustainability of different approaches to large-scale ITN distribution are urgently needed; in particular, more specifically, consistent meth-odologies and sufficient resources are needed to evaluate the large-scale approaches, such as voucher schemes, currently being supported by the Global Fund to Fight AIDS, Tuberculosis and Malaria.

3. There needs to be greater evaluation of the suc-cess of approaches to increasing accessibility of treatment (e.g. community agents, retail outlets, home-based care).

6. ECONOMIC EVALUATION5

National and international policy-makers require information on which strategies are best for preven-

4 This section draws on Hanson et al., 2003.5 This section draws on Goodman & Mills, 1999.


tion, how treatment should be improved, and wheth-er malaria control is a good investment compared with other health-care interventions. Methods for economic evaluation, and in particular cost–effec-tiveness analysis, can provide important informa-tion for identifying the interventions that represent the best value for money.

Unfortunately, the number of cost–effectiveness analyses on malaria control is very limited – glob-ally we know of only 14 different studies that report cost–effectiveness using generic health out-come measures, such as deaths averted or disability-adjusted life years (DALYs) (Goodman & Mills 1999; Hanson et al., 2004). Most are based on data collect-ed during trials, or use models to synthesize data from many different sources. Evaluations of routine service delivery are very rare. Country coverage is haphazard – and heavily related to the location of the main research institutions!

These few studies provide some guidance to deci-sion-makers, and indicate that many of our cur-rent control measures can be highly cost-effective relative to many other health-care interventions. However, the potential of these studies to inform policy debates is limited by the lack of evidence on the costs and effects of packages of measures, and the problems in generalizing or comparing stud-ies that relate to specific settings, and use different methodologies and measures of outcome.

While more studies are needed, in particular, focus-ing on new interventions and delivery modes in operational settings, this takes time and it will never be possible to perform studies in every possible sit-uation. This argues for further development of mod-elling approaches, which can provide a systematic analysis of variation in cost–effectiveness across dif-ferent epidemiological and economic zones. It is also essential that new studies are based on inter-national best practice in cost–effectiveness analysis, and report results in line with standardized cost–effectiveness guidelines to enhance comparability between studies (Gold et al., 1996).


1. Ensure that any evaluation of new tools for the control of malaria includes an economic compo-nent.

2. Increase evaluation of the cost–effectiveness of packages of control measures, including increas-ing the number of evaluations of malaria control in routine settings.

3. Expand efforts in application of modelling approaches to assessing cost–effectiveness.

7. EVALUATION AT THE WHOLE-SYSTEM LEVEL

There are many systems-level questions that have been barely touched on in the literature on malar-ia, although the general health economics literature does include relevant publications. These questions include:– What is the appropriate role of government in

malaria control and how can it be strengthened? – What are the efficiency and equity implications

of different ways of carrying out the govern-ment’s role?

– What regulatory approaches are appropriate and effective in influencing access to and provi-sion of prevention and treatment for malaria?

– What is the appropriate balance between public and private sectors for both financing and provi-sion?

Hanson (Hanson, 2004) examines economic thinking on the role of government and its relevance to malar-ia control, emphasizing that although market failure provides a justification for public intervention in a number of malaria control interventions, this con-ventional welfare economics approach does not pro-vide guidance about how governments should best intervene. Nor does it recognize that policy-mak-ers are likely to pursue a broader range of objec-tives than simple welfare maximization, including health maximization and poverty alleviation. This implies that an expanded set of information is need-ed to make resource allocation decisions, including information on costs and cost–effectiveness of inter-ventions, the nature of demand for interventions (including price and income elasticities), and the existence and performance (quality, accessibility) of substitutes for public provision. The complexity of the interactions among these dimensions means that it is not possible to arrive at simple, universally applicable guidelines on how governments should be involved malaria control.

Issues of government performance in malaria con-trol have received virtually no attention since the failure of eradication. Yet there are major issues – examined in general terms in the development eco-nomics literature – concerning the organization of public services (for example, degrees of decentral-ization) and influences on the performance of public sector workers. In countries heavily affected by HIV, there may need to be a radical reappraisal of what the public sector can feasibly do.

Regulation has been examined particularly in the drugs literature, and is now becoming an increas-ingly important issue given concerns over drug use


and quality. We know that antimalarial drugs are very widely available in the private sector, but only a few studies have explored issues of drug quality (Taylor et al., 2001; Risha et al., 2002) and prescrib-ing. (Oshiname & Brieger, 1992; Marsh et al., 1999; Stenson et al., 2001) and greater understanding is required of intervention points and possible public policy action.

The balance of public and private action has been discussed primarily in relation to ITNs. Key policy questions are the optimal degree of subsidy; the role of the private sector in production, distribution, and sales; and the extent to which markets can be seg-mented through targeted approaches, enabling pub-lic funds to be concentrated on those least able to pay. There has recently been a considerable increase in research on this topic, but a much greater num-ber of country studies are needed before clear con-clusions can be reached. As argued earlier, evidence is particularly required about the effectiveness of alternative approaches when operated at a suffi-ciently large scale.


1. Effectiveness of alternative ways of carrying out the government role in malaria control.

2. Success of various ways of strengthening regu-latory functions, especially relating to drugs.

3. With respect to both prevention and treatment: costs, effectiveness and feasibility of alternative nationwide approaches to targeting subsidies to vulnerable populations; costs and effectiveness of measures to encourage commercial sector expansion; impact of interaction of public and private delivery systems.

8. RESEARCH CAPACITY BUILDING

Lack of availability of economists is a major barrier to greatly increasing the number of economic anal-yses of malaria. Of all the disciplines required for high quality research on malaria, economists are probably most in short supply. Moreover, econo-mists attracted into health are more likely to work on broad health service issues rather than on spe-cific diseases such as malaria; and malaria research groups often experience difficulties in recruiting economists to join them. Young economists can gen-erally find relatively well-paid work outside health research, and remuneration for health economics research is not competitive with alternative options open to good young masters graduates.

McIntyre (McIntyre, 2002) argued that the following issues need urgently to be addressed if capacity is to be increased:

– Expansion of soft-funded research institutions that are not dependent on the very limited gov-ernment funding available.

– Introduction of programme funding, which includes adequate support for institutional costs.

– Greater opportunities for “on the job” experi-ence in malaria research.

– Adequate funding for capacity development within research projects.

– Strengthened postgraduate training in health economics and disease-specific applications.

– Support for networks that can link isolated researchers, and for conference attendance.

9. CONCLUSIONS

The above discussions make it clear that there is still a very large research agenda needing to be addressed, and prioritization is clearly called for. We would emphasize the following key priorities:– Evaluation of measures to improve access to malar-

ia prevention and treatment. In general terms, we know what the problems are and what might be the potential solutions; what we do not know is how well different approaches might work in particular country settings. Far more real-life experimentation is called for, and on a large scale: small-scale research projects are not often very helpful in informing national policy.

– Evaluation of measures to strengthen the perfor-mance of prevention and treatment services. Limited knowledge has gradually been gained on how the performance of private providers can be improved, but much more work is needed in this area; moreover the vital issue of improving public sector performance, and especially staff performance, requires much greater attention.

– Systematically addressing how best to reach the poor-est groups with preventive and treatment measures. An equity lens has been notably absent in most research to date; information relevant to equity should be collected in all evaluative research.

– In all these areas, greater attention must be given to increased methodological rigour, and to standardization of methods in key areas, such as measurement of SES, to enable findings to be compared across settings.

All these research priorities will require close collab-oration between research and control communities, and large-scale testing of approaches.


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Mal

aria

Annex 18 WORKING PAPER: Achievements, challenges and opportunities in malaria research


ACHIEVEMENTS, CHALLENGES AND OPPORTUNITIES IN MALARIA RESEARCH

Anders Björkman Division of Infectious Diseases Department of MedicineKarolinska HospitalStockholm, Sweden

1. EXECUTIVE SUMMARY

The international community increasingly acknowl-edges that malaria is a major public health prob-lem that urgently needs addressing, and a cause of poverty, and that prompt access to good treatment and prevention should be viewed as a basic human right. An international commitment to the problem and to the need for research is therefore emerging.

The burden of malaria has been significantly under-estimated and is even now increasing, largely due to technical and economic constraints in implement-ing control measures and to the spread of resistance to drugs. Rates of morbidity and mortality caused by malaria are especially high in small children and pregnant women in sub-Saharan Africa.

Malaria poses particular challenges for public health and research because of its great diversity. This diversity concerns the parasite in particular, but also the host, and the epidemiological, social, cultural and economic conditions faced by malaria control efforts. All this requires a much more inter-active approach to research than employed hither-to, including involvement of complementary fields of medicine.

The recent sequencing of the genomes of Plasmodium falciparum and Anopheles gambiae, and of the human genome provides an unprecedented opportunity for research and development of vaccines, new drugs and diagnostics. Researchers in the clinical, ento-mological, epidemiological and social sciences need to develop, evaluate and compare new as well as existing control strategies, such as use of insecticide-treated nets (ITNs) and residual spraying, intermit-tent presumptive treatment (IPT) during infancy and pregnancy, and home-based treatment, e.g. rec-tal formulations. New developments in information technology and bioinformatics and the extraordi-nary development of scientific capacity in countries

in which malaria is endemic offer an unprecedented basis for a comprehensive scientific commitment.

The time has come for the development of multidis-ciplinary research, for improved malaria control and for better health for those exposed to malaria.

2. INTRODUCTION

2.1 The burden of malaria

It is critical that the burden of malaria in Africa and elsewhere be acknowledged and adequate-ly assessed, not only so that the problem can be addressed effectively from a public health perspec-tive, but also so that it receives appropriate attention and resources with regard to research allocation and development.

This topic was comprehensively explored in a recent review (Breman, 2001). Malaria was shown to hin-der economic development and to be a cause of pov-erty, and not vice versa (Gallup & Sachs, 2001). A more specific microeconomic analysis of the impact of malaria on the productivity of individuals could not be undertaken considering the state of existing research, but it can be concluded that investment in malaria control could not only result in health improvement but also full cost recovery and even economic gain. Further studies are necessary to con-firm this, however.

General estimates of morbidity and mortality asso-ciated with malaria suggest that up to 25–30% of deaths in African children aged less than five years are caused by malaria, meaning that 5% of chil-dren born in Africa will die from malaria. A recent review on global mortality from malaria conclud-ed that the estimate of 1 million deaths in Africa was still valid (range, 0.75–1.30 million), with more than 75% of mortality attributable to malaria in children (Snow et al., 1999). More specific concerns have also been raised recently with regard to possible under-estimation of morbidity and mortality associated with malaria. These concerns relate to malaria and anaemia, pregnancy outcome, neurological sequel-ae and potential interactions with other diseases/infections. Also, the spread of chloroquine-resistant malaria has aggravated the morbidity and mortality caused by malaria, especially in sub-Saharan Africa (Snow et al., 2001; Trape, 2001), including causing epidemics (Warsame et al., 1995).

A persistently debated issue is the correlation of malaria transmission and malaria-associated mor-tality (Snow & Marsh 1995; Trape & Rogier 1996; Snow et al., 1997; Smith et al., 2001). It has been


argued that malaria control, i.e. reduction of trans-mission, may under some conditions result in high-er mortality due to reduced/delayed acquisition of immunity. Until proven otherwise, however, the most common belief is that higher rates of transmis-sion lead to higher rates of mortality.

The incidence of childhood anaemia in sub-Saharan Africa is high and its main etiological factor is falci-parum malaria. Increased resistance of Plasmodium falciparum to antimalarial drugs has further exacer-bated this problem (Björkman, 2002), and indeed has most probably caused increased mortality attribut-able to malaria in recent years (Snow et al., 2001). Since the most common reason for carrying out blood transfusion in this region is severe childhood anae-mia, the risk of blood-borne transmission of HIV, which is highly prevalent in the same area, adds sig-nificantly to the problem. Blood transfusion criteria are now being revisited in this context, but evidence-based data on effects/benefits of blood transfusion in relation to severity and clinical manifestations of anaemia are lacking. Although anaemia is surely a major contributor to mortality, especially in the very young (aged less than two years) in areas in which malaria is highly endemic, data from Kenya suggest that the other main severe manifestations of malar-ia, i.e. cerebral malaria and respiratory distress are more commonly fatal (Marsh et al., 1995). Anaemia, however, is a major contributor; a combination of two or three manifestations is highly associated with fatal outcome. The least investigated and recognized manifestations of malaria are the short- and long-term effects on cognition and behaviour. Recent data suggest that these effects may be highly significant, especially after severe malaria in children with neu-rological and/or cognitive sequelae.

The potentially deleterious effects of falciparum malaria in pregnancy, especially first-time pregnan-cy, have been acknowledged for some time; these effects include increased risks of abortion, stillbirth and reduced birth weight. However, the magnitude of this public health problem may have been under-estimated. It was recently estimated that as many as 75 000–200 000 infant deaths may be linked to, i.e. at least partly caused by, malaria in pregnancy (Steketee et al., 2001), and each year 400 000 preg-nant women may develop malaria-associated severe anaemia, with a resulting large death toll (Guyatt & Snow, 2001).

2.2 The global response

It is in the context of this heavy burden on health and the resulting impediment to socioeconomic devel-

opment that the international community is becom-ing increasingly committed to malaria control.

The first step was taken when the New Global Strategy was presented in 1992 and malaria was re-established as a global health priority by the Conference of Ministers of Health in Amsterdam. This was followed by the project Accelerated imple-mentation of malaria control (1997–1998), which main-tained an unprecedented focus on and support for the fight against malaria in Africa. The next step was the launching in October 1998 of the “Roll Back Malaria” initiative, setting the agenda for a compre-hensive global commitment until 2010, and includ-ing general goals that were specified for the African continent at the Abuja Malaria Summit in April 2000. According to the “Abuja targets”, it was concluded that by 2005:– 60% of malaria patients should have access to

affordable and appropriate treatment within 24 hours;

– 60% of children aged less than five years should benefit from ITN coverage;

– 60% of pregnant women should have access to both IPT and ITN;

– 60% of epidemics should be detected within two weeks and acted upon within the subsequent two weeks.

2.3 The scientific challenge

The Roll Back Malaria (RBM) initiative is primarily based on existing tools, policies and strategies, but it is evident that the scientific community also needs to commit to providing evidence on how to improve the use of existing tools, as well as urgently provid-ing development of new tools for the future fight against malaria.

Malaria represents a special public health and research challenge, largely because of its huge potential for diversity, which allows it to escape from the two main enemies of the parasite in the host, i.e. the immune system and the antimalarial drug. Malaria control is also faced with major diver-sities with regard to epidemiological, social, cultural and economic conditions, which need to be consid-ered in optimal control strategies. This requires a much more interactive research approach than hith-erto employed, and should include complementary fields of medicine.

The challenge posed by malaria thus requires strong and interactive responses from the basic, clinical and social sciences. The scientific community needs to address the dynamics of the host, the parasite and the interventions at all levels, from the molecule in


the parasite to the patient in the community. This is actually being done increasingly, with interesting developments. It is, however, also essential to per-sistently maintain a humble realization of the ability of the parasites to adapt to our interventions.

The recent sequencing of the genomes of Plasmodium falciparum and Anopheles gambiae, and of the human genome provides a hitherto unprecedented oppor-tunity for research on and development of new tools against malaria. New potential targets and leads for drug development are being identified, candidate vaccine components are being developed and test-ed, and genetic manipulations affecting the vecto-rial capacity of the mosquito are being identified. Clinical, entomological, epidemiological and social sciences are identifying and evaluating new control strategies, such as use of ITNs, IPT during infancy and pregnancy, and home-based treatment, includ-ing rectal formulations. All this, together with new developments in information technology and bioin-formatics and the extraordinary development of sci-entific capacity in the endemic countries now offers an unprecedented basis for a broad and ambitious scientific commitment to meet and overcome the public health challenge of malaria, the disease of the poor.

The time of poor malaria control for poor people is over. The scientific community has to accept its responsibility and build on today’s unique opportu-nities for successful research into malaria.

3. ACHIEVEMENTS

3.1 Entomology and vector control

Past experience

There are a number of potential ways by which the transmission of parasites to the human host can be reduced. Broadly, they can be divided into preven-tion of human-vector contact, reduction of mosquito populations, and reduction of the vectorial capaci-ty of anopheline mosquitoes. The three main malar-ia vectors in Africa are A. gambiae senso strictu, A. arabiensis (belonging to the A. gambiae complex) and A. funestus. Genetic studies have, however, identi-fied at least seven related, but genetically and eco-logically distinct, subspecies (Collins et al; 2000, Gentile et al., 2001). The recently described A. gam-biae sequence (Holt el al., 2002) now provides the opportunity to associate and understand genetic dif-ferences with regard to factors such as vector behav-iour and capacity.

The prevention of human–vector contact includes general human behaviour, changes in the immediate

environment, local repellents and the use of mosqui-to-proof bednets, especially when impregnated with insect repellents or insecticides. The use of ITNs has had a significant and possibly sustainable effect in areas in which malaria is highly endemic and has been a focus of interest in the last 15 years. Trials have demonstrated an efficacy of 14–42% in terms of (crude) mortality in children aged less than five years (Alonso et al., 1991; D’Alessandro et al., 1995; Binka et al., 1996; Nevill et al., 1996; Habluetzel et al., 1997; Phillips-Howard et al., 2003). The use of ITNs is now widely recommended, especially for vulnerable groups such as small children and preg-nant women. This is therefore recommended as a major strategy within the RBM initiative, especial-ly for vulnerable groups such as small children and pregnant women. The majority of ITN programmes employ pyrethroid insecticides. There are several major issues in the context of use of ITNs on a large scale. The first regards deployment, i.e. whether the ITNs are to be provided at full cost, subsidized or free of charge (Hawley et al., 2003; Nahlen et al., 2003; Curtis et al., 2003).

Besides operational questions, two key issues need to be addressed with regard to ITNs, as for residu-al spraying. One concern is to what extent reducing transmission entails a risk of a rebound effect owing to decreasing herd immunity. Reported studies have so far not been fully conclusive, showing both sig-nificant decreases in levels of antibodies to parasite surface antigens (Askjaer et al., 2001) and a more mixed picture depending on the antigen assessed and target populations (Kariuki et al., 2003a, 2003b). Another concern is the potential for development of resistance to the repellents/insecticides (Collins et al., 2000).

The reduction of mosquito populations can be directed towards adult mosquitoes and/or the lar-vae. The main strategy has been to target the adult mosquito population by spraying with insecticides, mainly indoors. This has resulted in significant reduction and even elimination of malaria vectors in many areas after the implementation of the malar-ia eradication programme in the 1950s. In areas of high transmission it proved, however, to be diffi-cult/not achievable, although a few examples of rel-ative success were reported after massive and thus resource-demanding efforts (Hedman et al., 1979; Molineaux & Gramiccia, 1980). The anopheline mos-quitoes have responded to challenge by insecticides by changing behaviour (resting and feeding habits) and by developing resistance to the different com-pounds used. The use of insecticides in agriculture has strongly contributed to this development. In addition, ecological concerns with regard to use of


insecticide in agriculture have also had implications for use of insecticides for indoor residual spray-ing (IRS) to prevent vector-borne infections such as malaria. Hence, IRS has received significantly less attention and promotion in recent years, although the ecological implications of IRS are much less obvi-ous than for agriculture spraying. Larval control has included mechanical methods, but also application of chemical agents, i.e. larvicides, larvivorous fish or toxin-producing bacteria (Bacillus thryringiensis). While these methods have had effects under certain ecological situations, success has been very limited in highly-endemic situations.

Reduction of the capacity of anophelines to act as vectors, i.e. to carry malaria parasites, represents a recent area of interest in view of our increased understanding of the reasons for refractoriness of mosquitoes for the parasite and the potential for genetic manipulations of mosquitoes to induce such refractoriness (see ‘New developments’ below).

Insecticide resistance

Spread of resistance to the existing insecticides espe-cially pyrethroids, among anopheline mosquitoes, represents a major concern for future vector con-trol. Unfortunately resistance to pyrethroid-treat-ed bednets has now been recorded in different parts of Africa in A. gambiae populations, as well as in A. funestus, the other main vector in Africa. Understanding the mechanisms of resistance is therefore of vital importance. Resistance to insectide is most commonly the result of changing target site or increased metabolism of insecticide. Cross-resis-tance represents a special problem for two impor-tant insecticides: DDT and pyrethroids, since they have same target site.

Up-regulation of groups of insecticide-detoxifying enzymes represents the main mechanism of resis-tance. A limited number of enzyme families, such as cytochrome P450s, carboxylesterases and gluta-thione S-transferases, are involved in this process (Hemingway et al., 2002). The glutathione trans-ferases have been implicated in resistance to DDT, the carboxylesterases in resistance to organophos-phate and carbamate insecticide, whereas the cyto-chrome P450s have been implicated in resistance to pyrethroid. Comparative genomic analysis with Drosophila melanogaster has revealed that a consid-erable expansion of these supergene families has occurred in the mosquito, consistent with major dif-ferences in the ecology of these organisms (Ranson et al., 2002). Sequencing of the A. gambiae genome has now provided an unprecedented situation for the elucidation of the roles these protein families

play in resistance to insecticide (Hemingway et al., 2002).

One means to counteract and reverse resistance to current insecticides would be to add compounds specifically targeting the three protein families. An inhibitor of cytochrome P450-mediated detoxifica-tion of pyrethroids is piperonyl butoxide (Devine & Denholm, 1998). This compound is unlikely to be approved for use in combination with pyrethroid for the treatment of nets, since it has also been shown to have inhibitory effects on human P450s (Franklin, 1976).

An additional mechanism of resistance that is of major concern is the knock-down resistance phe-notype or kdr. Resistance is caused by mutation in the voltage-gated sodium channel of the insect ner-vous system, a target for both pyrethroids and DDT (Martinez-Torres et al., 1998; Ranson et al., 2000). Interestingly, however, this does not affect the impact on the density of the vector population or on sporo-zoite rates and malaria parameters (Darriet et al., 2000). One possible explanation is that the kdr gene causes pyrethroids to have reduced qualities of irri-tability, allowing longer contact between the insec-ticide and the mosquito, and thus having a greater killing effect, despite partial resistance.

New developments

The availability of the sequence of the A. gambiae genome (Holt et al., 2002), as well as that of D. mela-nogaster (Adams et al., 2000) will obviously provide opportunities for new developments in vector con-trol. The search for new targets for insecticides is one such opportunity. Several potential targets relat-ed to the endocrinology or neurogenesis of the mos-quito have already been identified (Ranson et al., 2002; Riehle et al., 2002). Another approach is to tar-get the host-seeking or feeding capacity of the mos-quito, i.e. the odorant binding proteins (Hill et al., 2002; Vogt, 2002).

Genetic interference with reproduction by means of the release of a modified insect population repre-sents a new alternative for the reduction of vector populations. One possibility is the release of ster-ile males. Since females of many insect species usu-ally mate only once, mating with a sterile male will inhibit growth of the population. This technique has already been applied in a few settings with suc-cessful results. However, it is only effective when the insect population is relatively small, i.e. smaller than that of the mass-produced and released sterile males (Alphey & Andreasen, 2002). Another genetic alternative is the release of insects carrying a dom-


inant-lethal gene (Heinrich & Scott, 2000; Thomas et al., 2000). Here the lethal gene is expressed only in females (i.e. its product kills females only) and is effectively repressed during mass production (before release) by a compound that does not occur in nature (e.g. tetracycline). Altogether, it must be realized that the effectiveness of ”sterile insect tech-nique” is dependent on insect population structure and dynamics and is unlikely to be effective in areas of Africa in which malaria is highly endemic.

Specific genetic manipulation of vectorial capacity represents an additional potential means to more directly reduce the transmission of malaria. Since D. melanogaster was first genetically transformed, trans-formation of many other insects, including A. ste-phensi and A. gambiae, has also been accomplished. The transformation of promoters could result in abundant transcription, and subsequent synthesis and secretion, for instance, in the midgut lumen or the salivary gland, of specific proteins that are harm-ful to the development and life-cycle of the parasite. Another genetic manipulation could involve the introduction of effector genes whose products inter-fere with the development of the malaria parasite. Examples include: a peptide targeted at parasite receptors in the mosquito (Ito et al., 2002); phospho-lipase A2, which interferes with ookinete invasion in the midgut (Moreira et al., 2000; Zieler et al., 2001); monoclonal antibodies that bind to the parasite (de Lara Capurro et al., 2000); and peptides associat-ed with insect innate immunity, e.g. defensins and cecropins that are directly toxic to the parasite.

While in a laboratory setting mosquitoes have been successfully modified and thus impaired in their ability to transmit malaria, several obstacles need to be dealt with before this technique can be applied in the field. The first problem is that the fitness of genetically modified mosquito will normally be reduced (Cateruggia et al., 2003). Hence, mosqui-toes that were transgenic for phospholipase A2 were found to produce fewer eggs than normal mosqui-toes (Jacobs-Lorena, 2003). Transgenic mosquitoes may have to incorporate several effective genes in order to prevent the parasites from becoming resis-tant to the inhibiting products.

3.2 Pathogenesis and immunology

The pathogenesis of malaria is broadly caused by: (a) destruction of erythrocytes and release of par-asite and erythrocyte material, and related immu-nological reactions; and (b) sequestration of P. falciparum-infected erythrocytes in the microcircu-lation (“cytoadherence”), leading to microcirculato-ry obstruction.

The destruction of erythrocytes is partly caused by intravascular haemolysis, but mostly by extravas-cular elimination, including largely non-parasit-ized erythrocytes (Ekvall et al., 2001b; Egan et al., 2002; Price et al., 2001). Phagocytosis, especially after sequestration in the spleen, is probably relat-ed to the production of cytokines and possibly anti-gen–antibody complexes in response to the malaria infection (Kurtzhals et al., 1998; Waitumbi et al., 2000; Griffiths et al., 2001).

Upon rupture of the erythrocyte, malaria antigens are released, and cytokines and other immune reac-tions are activated. Tumor necrosis factor (TNF) has been associated with severe malaria (Grau et al., 1989; Kwiatkowski et al., 1990) and clinical symp-toms (Bate et al., 1989), especially during rigours of P. vivax infections (Karunaweera et al., 1992). Cytokines are also believed to be involved in the pathogenesis of malaria by causing suppression of erythropoiesis (Clark & Chaudhri, 1988). Anaemia that follows the destruction of erythrocytes is fur-ther aggravated by impaired reproduction of eryth-rocytes caused by bone marrow dysfunction, which is also particularly associated with chronic infec-tion with malaria. The dysfunction may be caused by bone marrow suppression or ineffective eryth-ropoiesis (Menendez et al., 2001; Verhoef et al., 2001). Cytokines may also be involved in this patho-genesis (Clark & Chaudhri, 1988; Martiney et al., 2000). Production of oxygen radicals (Greve et al., 2000) or nitric oxide, and macrophage dysfunction (Schwarzer et al., 1992) have also been implicated in the bone marrow dysfunction.

The cytoadherence of P. falciparum-infected eryth-rocytes to microvascular endothelium, i.e. it is believed that sequestration is probably the major cause of the pathophysiology. Cytoadherence occurs predominantly in venules of vital organs, but not uniformly in the body. Different affinities to differ-ent receptors may vary for different parasites and hosts. Pathogenic reactions may thus occur in dif-ferent organs, mainly as a result of microcirculatory obstruction and thus reduced oxygen and glucose supply, leading to anaerobic glycolysis and lactic acidosis (White & Ho, 1992).

Cytoadherence is mediated by a family of high molecular weight parasite-derived proteins, includ-ing P. falciparum erythrocyte membrane protein-1 (PfEMP-1) (Magowan et al., 1988; Howard & Gilladoga, 1989). This protein is exported to the sur-face of the infected erythrocyte. The receptors to such proteins are found on the vascular epithelium and several of them have been identified (e.g. CD36, TSP, ICAM-1). Binding of CD36 and ICAM-1 involves


specific but distinct PfEMP-1 sequences (Baruch et al., 1999). Erythrocytes that contain mature P. fal-ciparum parasites also adhere to uninfected eryth-rocytes, causing so-called “rosettes” (David et al., 1988; Udomsangpetch et al., 1989). Human cerebral malaria has been found to be associated with such rosetting of erythrocyte and also lack of anti-roset-ting antibodies (Carlson et al., 1990), suggesting that this process has a role in the pathogenesis of severe malaria.

Antigen variation, e.g. in PfEMP-1, represents an important virulence factor that facilitates evasion of the parasite from the immune response of the host (Newbold, 1999), possibly especially allowing par-asite growth in the case of chronic infection (Saul, 1999). The cytoadherence of the infected erythro-cyte may in turn protect the parasites from destruc-tion in the spleen. Adherence to dendritic cells may also lead to modulation of the latter in their matura-tion and an impairment of the antiparasitic immune response (Urban et al., 1999). On the other hand, erythrocytes with mature parasites become more rigid (Cranston et al., 1984). This, as well as immu-nological reactions towards antigens on the erythro-cyte cell surface, will increase the clearance of these infected erythrocytes from the blood circulation, mainly by the spleen.

Malaria infection induces both humoral and cellular immune responses. There is significant production of both species-specific and stage-specific antipar-asite antibodies that react with a large number of antigens. Passive transfer of immunoglobulins to non-immune recipients has provided evidence of a protective effect, with antibody-dependent activa-tion of monocytes possibly playing a major role. The immune responses induced by malaria infection are, however, influenced by both environmental and genetic factors (Modiano et al., 1999). In addition, the role of concomitant infection needs to be clari-fied in this context. Besides the species-speific and stage-specific humoral response, there is also non-specific polyclonal B-cell activation and a resulting hyper gamma-globulinaemia, mostly of antibod-ies that are not malaria-specific. This is believed to interfere with the development of more specific cel-lular immune responses (Ho & Webster, 1990).

The major players in the cellular immune response to malaria are lymphocytes and mononuclear phagocytes. When activated, they perform protec-tive effector functions, such as antibody production, cellular cytotoxicity and phagocytosis. Their inter-actively regulated balance is primarily controlled by cytokines, produced by the activated cells. The bal-ance between pro- and anti-inflammatory cytokines

in turn will have a major impact on the outcome of a malaria infection (Day et al., 1999). The variation in cellular as well as the humoral responses will have significant implications for vaccine development (Perlmann & Björkman, 2000) (see 3.5).

3.3 Clinical manifestations

Severe malaria

Severe malaria affects several tissues and organs, even if the dominant manifestation in a single patient may involve one organ, e.g. the brain. The three dominating manifestations related to fatal out-come in children appear to be cerebral malaria, acute respiratory distress syndrome (ARDS) and severe anaemia. The prognosis is especially severe in ARDS and when the manifestations are combined (Marsh et al., 1995). Generally, metabolic acidosis is increas-ingly recognized as a critical clinical feature.

Cerebral malaria and especially unconsciousness, was believed in the past to be due to cerebral oede-ma, but modern radiological investigations with computerized tomography and magnetic resonance imaging have not shown any clear evidence of this (Newton et al., 1994; Looareesuwan et al., 1995). The cause of coma is, however, still not very clear. There is reduced arterial oxygen, increased cerebral spinal fluid concentrations of lactate (Warrell et al., 1988), and increased intracranial pressure, but this does not provide a full explanation for coma (White & Ho, 1992). Other factors such as cytokines, neural trans-mission and nitric oxides may be involved (see also 3.2). A better understanding of the pathophysiology of cerebral malaria is essential, since recent advanc-es have not been sufficient to lead to improved treat-ment (White, 1998a).

Neurologic or cognitive sequelae, which may be lifelong, are found in 5–20% of survivors of cere-bral malaria, especially after seizures and sta-tus epilepticus (Holding & Snow, 2001). However, whereas intramuscular administration of phenobar-bital does reduce seizure frequency, mortality slight-ly increased, maybe as a result of other effects of the drug, i.e. respiratory depression (Crawley et al., 2000). Low birth weight caused by malaria during pregnancy may also potentially impede cerebral development (Taylor, 1984).

Microvascular obstruction is probably also impor-tant for pathophysiological reactions in other organ failures. Sequestration in the gut appears to be a major reason for gastrointestinal dysfunction. Renal failure is another example, although the massive haemolysis associated with blackwater fever (malar-ial haemoglobinuria, a complication of falciparum


malaria) has its own, not fully elucidated, patho-genesis, which is especially associated with treat-ment with quinine and with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The pathogen-esis responsible for some organ dysfunctions, such as pulmonary oedema and ARDS, remain largely unclear.

Severe anaemia in P. falciparum malaria has received significantly less research attention than has cerebral malaria, although it may be at least as important from a public health perspective. The development of severe anaemia and indeed malarial anaemia in general is complex (Ekvall, 2003). It involves eryth-rocyte destruction and bone marrow dysfunction (see 3.2). A wide variation is observed in mortali-ty in children with haemoglobin concentrations of less than 50 g/l (Brabin et al., 2001). Blood transfu-sion is urgently required when anaemia is associat-ed with incipient or established cardiac failure, but data on criteria for indication are lacking (English et al., 2002).

Chronic malaria

The health implications of chronic asymptomat-ic and/or recurrent uncomplicated malaria are still not fully clear. Clearly, exposure to different lev-els of parasitaemia over time will determine hae-moglobin concentrations and give rise to different degrees of anaemia, especially in infants/small chil-dren (McElroy et al., 2000; Ekvall et al., 2001a). To what extent this malaria-associated anaemia causes health problems and/or deficits in cognition, per-formance etc. remains unsettled (Holding & Snow, 2001), although an association has been found in children with iron deficiency and anaemia (Stoltzfus et al., 2001).

Splenic enlargement is a general feature in recur-rent malaria and chronic infections. Under certain conditions, the hypersplenism may even result in a pathogenic syndrome called tropical splenomega-ly syndrome. Genetics of the host and/or epidemio-logical conditions appear to play a role.

Malaria in pregnancy

In areas in which malaria is endemic, pregnancies are associated with increased susceptibility to P. fal-ciparum infection affecting the mother (fever epi-sodes, anaemia), but especially the fetus (see below). The effects are particularly prominent in primigrav-idae. Pronounced sequestration of erythrocytes that are infected with mature parasites in the intervillous spaces of the placenta will lead to placental insuffi-ciency and retarded fetal growth, which may result in low birth weight, risk of stillbirth and increased

frequency of spontaneous abortions. The increased susceptibility of the mother to malaria may also be due to suppressed immune responses to malaria during pregnancy (Riley et al., 1989). Several stud-ies have provided evidence for the corresponding health benefits of preventing malaria during preg-nancy by chemoprophylaxis or vector control, e.g. ITNs (ter Kuile et al., 2003).

The accumulation of parasites is believed to reflect cytoadherence to placental syncytio-trophoblasts (Ismail et al., 2000). Available evidence indicates that the major, but perhaps not the only, placental host receptor in these cases is chondroitin sulphate A (CSA) (Maubert et al., 2000; Gysin et al., 1999; Reeder et al., 1999; Buffet et al., 1999). CSA-binding para-sites are not found in women who are not pregnant, and probably represent variants that are distinct both antigenically and with regard to their adhe-sive properties (Beeson et al., 1999). Multigravidae have developed antibodies that inhibit CSA-depen-dent cytoadherence (Maubert et al., 1999) and are less susceptible to placental malaria.

Malaria and other infections

A subject which has received much too little atten-tion is the general interaction between malaria and other infections. This is important since children in sub-Saharan Africa especially are exposed to a range of other infections concomitantly with malaria. In the few studies reported to date, viral infections such as measles and influenza have been shown to reduce malaria parasitaemia (Rooth & Björkman, 1992a) whereas infection with HIV/AIDS has been shown to exacerbate the malaria infection (Whitworth et al., 2000). A recent study suggests that helminthic infections are associated with protection from cere-bral malaria (Nacher et al., 2002).

Malaria also has the potential to affect the outcome or manifestations of other infections. Placental malaria has been shown to increase the risk of vertical HIV transmission from mother to fetus. However, wheth-er malaria also hastens the development of AIDS in the HIV-infected individual has not yet been deter-mined.

Patients with severe malaria are traditionally vul-nerable to bacterial infections. This may result in pneumonia, urinary tract infections and also sep-ticemia. The latter is mainly caused by gram-nega-tive infections, and probably results from erosions in the mucosa as a result of intense sequestration. Salmonella septicemias are even relatively frequent in uncomplicated falciparum malaria in African children (Mabey et al., 1987).


Diagnosis of malaria

The diagnosis of malaria, or rather the identifica-tion of the malaria infection that requires treatment, is fundamental in malaria control. Its specificity has become increasingly important, in view of the evo-lution of drug resistance, due to the need for more complex and expensive alternative treatments and for restricted use of the drugs to prevent further resistance. Microscopy at peripheral health-care level is associated with technical problems. Several rapid diagnostic tests for malaria using immuno-chromatographic methods have therefore been developed with detection capabilities almost com-parable to those commonly achieved by microsco-py. The tests still have constraints, however, mainly costs, partial lack of species specificity and partial lack of sensitivity.

Many attempts have been made to identify algo-rithms of symptoms and signs in the diagnosis of clinical malaria. However, the predictive values of such algorithms have generally not been sufficient to provide a basis for restricting the use of antima-larial treatment in febrile illness (Chandramohan et al., 2002). The overlap in clinical features of pneu-monia and malaria in particular in African children has represented a major diagnostic constraint.

3.4 Chemotherapy and drug resistance

General aspects

Chemotherapy for malaria broadly includes treat-ment of complicated and uncomplicated acute malaria, but also presumptive (preventive) treat-ment, as well as regular chemoprophylactic use of antimalarial drugs. The target groups of the lat-ter are specially susceptible and vulnerable groups such as pregnant women, non-immune travellers to endemic areas, immunosuppressed individuals (e.g. people with AIDS or that have been splenec-tomized), or individuals who are subject to specif-ic reactions to malaria infections (e.g. with sickle cell anaemia, tropical splenomegaly syndrome). Additional groups are also now being consid-ered, such as infants and small children who may be predisposed to severe malaria-associated anae-mia. Clearly these different situations/conditions will affect the choice (and development) of optimal drugs. This choice will also be affected by the esti-mated (partial) immunity to malaria in a given indi-vidual, since immunity is known to interact with chemotherapy (Björkman, 1988).

Existing antimalarial drugs can be categorized into quinolines, artemisinins, antifolates and antibiotics. Several of these drugs have been in clinical use for

many years, but their pharmacological properties have only recently been fully investigated. These studies have not, however, covered all groups of patients, e.g. all age groups and all ethnic popula-tions. Pharmacogenetic and thus also pharmacoki-netic profiles may indeed vary significantly between populations. This in turn may result in significant differences in efficacy and toxicity. An example is the uniquely high frequency of CYP2C19 muta-tion in Vanuatu and the consequent uniquely high frequencies of individuals who do not metabolize the antimalarial proguanil to its active metabolite (Kaneko et al., 1997, 1999a, 1999b).

Drug resistance

Chloroquine emerged on the scene and was found to be superior to other antimalarials in the 1940s. It became the cornerstone of antimalarial chemother-apy and the malaria eradication concept, due to its virtues of high effectiveness, low toxicity and low cost. Chloroquine-resistant falciparum malaria first developed and spread in south-east Asia and South America and then across Africa during the 1980s. Eventually chloroquine-resistant vivax malaria was also reported, first in Indonesia and then in sever-al areas of south-east Asia. Alternative antimalari-al drugs have become first-line treatments in areas of chloroquine resistance; resistance has eventual-ly also developed to these drugs. Thailand now rep-resents the worst-case scenario (Wongsrichanalai et al., 2001). There, efficacy has been partly or fully lost for all alternative monotherapies, with the excep-tion of the artemisinin derivatives, which came into wide use in the 1990s and then only as a combina-tion therapy mainly with mefloquine as partner drug. In Africa, the efficacy of alternative drugs may well evolve in the same way as in Thailand.

There is currently no evidence for clinically relevant parasite resistance to the artemisinin derivatives. However, artemisinin resistance has been induced and described in laboratory strains of P. falciparum (Inselburg, 1985) and P. yoelii (Peters & Robinson, 1999).

Drug-resistant malaria has increasingly become the major obstacle to malaria control (Björkman & Phillips-Howard, 1990; Wernsdorfer, 1994; Molyneux, 1999; Wongsrichanalai et al., 2002). It has resulted in increased morbidity and mortality, espe-cially in African children (Trape, 2001; Snow et al., 2001).

For Africa, the present situation is that chloroquine has been or needs to be replaced by alternative drugs in most parts of the continent. As a result, resistance


is now also rapidly eroding the efficacy of sulpha-doxine/pyrimethamine (SP), the most commonly chosen alternative (Sibley et al., 2001). Despite its similarities to SP, the combination of chlorprogua-nil and dapsone (“Lapdap”) has shown better effi-cacy and is being suggested as a useful alternative (Winstanley, 2000). Similarly, amodiaquine appears to still maintain enough efficacy to support its use in view of only partial cross-resistance with chlo-roquine, despite their perceived similarities, both being 4-aminoquinolines (Olliaro et al., 1996). The risk of agranulocytosis upon repeated intake of the drug for prophylaxis in travellers, however, still remains a concern and the potential risks associat-ed with repetitive intake of treatment doses by small children with frequent fever episodes, need to be elucidated. Resistance to quinine has not yet been documented in Africa, although it appears that a rel-ative decrease in susceptibility follows the develop-ment of resistance to chloroquine (Björkman et al., 1991). Mefloquine and halofantrin are of limited or no interest to Africa because of high costs and long elimination half-life and toxicity, respectively.

General relationships between widespread use of different antimalarial drugs, malaria transmission and different drug-resistant profiles have been part-ly documented (Watkins & Mosobo, 1993; White, 1998b; Price et al., 1996) and attempts are being made to try to model these interactions (Hastings & D’Alessandro, 2000). In vitro models that mimic the situation in vivo (Bwijo et al., 1997) and more in-depth, dynamic studies in vivo (White, 2002) need to be pursued to improve the understanding of evo-lution, persistence and dynamics of drug resistance, including the principles governing the survival fit-ness of drug-resistant parasites.

With regard to the molecular basis of resistance, the picture is clearest for the antifolates, especial-ly SP, but less clear for the aminoquinolines, main-ly chloroquine (Djimde et al., 2001). Interestingly, the mutations in pfmdr1 associated with resis-tance to mefloquine may also be associated with decreased sensitivity to artemisinin (Price et al., 1999; Duraisingh et al., 2000; Reed et al., 2000).

Molecular epidemiology has provided some recent evidence from Malawi on the issue of the survival fit-ness of drug-resistant parasites. After withdrawal of chloroquine as first-line treatment, the high frequen-cy of mutations associated with chloroquine resis-tance was reversed/decreased concomitantly with some apparent increase in susceptibility to chloro-quine in vitro and in vivo (Mita et al., 2003; Kublin et al., 2003). This would support previous, still con-troversial, findings of increased chloroquine suscep-

tibility in Viet Nam after withdrawal of chloroquine. The overall epidemiological picture, however, may suggest that chloroquine-resistant parasites may have a high survival fitness in view of their prop-agation worldwide and in areas not always obvi-ously associated with use of chloroquine. In mice, anecdotal findings suggested that chloroquine-resis-tant P. berghei parasites have a high survival fitness (Rosario et al., 1978).

A major problem is the ability of P. falciparum to develop multidrug resistance. This is of special con-cern since there are already indications that multi-drug-resistant parasites have an increased general ability to develop resistance to other novel drugs with novel modes of action. These issues further touch on the question of adaptation and compen-satory mutations after mutations conferring drug resistance have occurred. This has been described in bacteria. The opposite has been described for HIV. Lower replication rates are found in multi-drug-resistant HIV, resulting in slower progression towards AIDS. This, importantly, therefore supports continuous use of the therapy, even in the situation of resistance.

Molecular studies of drug resistance have been greatly enhanced by the recent development of tech-niques to perform stable transfection of P. falciparum. The role of particular genes and, more specifical-ly, the nature of specific mutations in different resis-tance phenotypes can now be studied and described. For example, with the allele-replacement approach it was possible to show that the suggested candi-date genes Cg1 and Cg2 were probably not involved in resistance to chloroquine, while a mutation in Pfcrt was likely to be critical for the chloroquine-resistant phenotype (Fidock et al., 2000a, 2000b). Further advances in molecular genetic tools are, however, necessary to facilitate the further elucida-tion of drug resistance. This includes multiple-gene targeting experiments using a double cross-over recombinant approach, positive/negative selection technology for “hit and run” mutagenesis and ran-dom library screening of transfectants (Crabb, 2002). General technological improvement required may be obtained by the inclusion of stretches of P. falci-parum, subtelomeric repeat sequence Rep20 in trans-fection plasmids (O’Donnell et al., 2002).

Combination therapy

Drug combination therapy (White, 1998b) is now increasingly recognized as a key response to the chal-lenge of drug resistance. The principles on which combination therapy rests are increased efficacy, prevention of drug resistance and possibly reduced


doses and duration, i.e. better tolerability and com-pliance. The theory behind the prevention of drug resistance in particular is that fast reduction of par-asite biomass will minimize the risk of mutations occurring, which may have to happen at several sites simultaneously to confer resistance to combi-nation therapy. Optimally, two drugs with full or at least very high sensitivity should therefore be com-bined. The drugs should have unrelated modes of action and no negative pharmacodynamic interac-tions on efficacy or tolerability. Synergistic activities of artemisinin-based drug combinations have been confirmed in vitro with mefloquine, lumefantrine and amodiaquine (Bwijo et al., 1997; Hassan Alin et al., 1999; Gupta et al., 2002a, 2000b), but further stud-ies are needed. Combination therapy should also be affordable and have a sufficiently simple regi-men. In Africa, two artemisinin-based combinations that are increasingly advocated are amodiaquine/artesunate and artemether/lumefantrin (Coartem). Other combinations of recent interest are dihydro-artemisinin/piperaquine and artesunate/chlorpro-guanil/dapsone.

The principle of combination therapy has been suc-cessfully applied in chemotherapy for tuberculosis (Grosset, 1980), HIV/AIDS (Montaner et al., 1999), leprosy and certain cancers. However, the experi-mental evidence for the benefits of combination therapy in malaria is scanty. In the animal model, combination therapy delayed the selection of resis-tant mutants (Peters, 1985). Some evidence is emerg-ing from Thailand that after wide-scale introduction of artemisinin plus mefloquine, not only has effica-cy remained, but possibly resistance to mefloquine alone has been halted (Brockman et al; 2000, Nosten et al., 2000) and possibly even reversed, although this obviously needs further documentation. In addition, the gametocytocidal effect of artemisinin-derived drugs seems to be sufficient to provide a reduction in transmission as a secondary benefit (Price et al., 1996).

3.5 Development of vaccines and drugs

The genomic era

By the end of 2002, malaria research had entered into a new era. The sequence of the human genome had just been published (Lander et al., 2001; Venter et al., 2001), and the 25 million base pairs (Mb) of P. falciparum (clone 3D7) (Gardner et al., 2002). Moreover, the sequence of the genome (2 600 Mb) of Anopheles gambiae, the most important mosquito vec-tor for human malaria in sub-Saharan Africa, was published almost simultaneously (Holt et al., 2002). The sequence of the genome of P. yoelii, a rodent parasite, of importance for experimental research

in the mouse model, as well as the sequence of the mouse genome are also expected to be made avail-able shortly.

The sequenced P. falciparum genome comprises 14 chromosomes containing about 5 000 genes (Gardner et al., 2002). The sequences of chromosomes 2 and 3 were actually published a couple years previ-ously (Gardner et al., 1998; Bowman et al., 1999). Genomic information has also previously been pro-vided for the mitochondrial genome (6 kb) (Feagin et al., 1991) and the circular plastid-like DNA (35 kb) in the organelle called the apicoplast (Wilson et al., 1996). The publicly available sequence data are now expected to provide the basis for the identification of important leads/targets for drugs (Ridley, 2002) and vaccines and generally to improve our understand-ing of functions, host interactions and the evolution-ary adaptation of the P. falciparum parasite. Indeed, there are already early examples of this (Roberts et al., 1998; Surolia & Surolia, 2001; Jomaa et al., 1999).

Vaccines

Conceptually there are three targets for malaria vaccines. The vaccine can aim to prevent infection (anti-sporozoite or liver-stage vaccine), at reduc-ing disease (anti-blood-stage vaccine) or at block-ing transmission (anti-gametocyte vaccine). The development of a vaccine against malaria and, more specifically, against P. falciparum infection and dis-ease generally is faced by a number of constraints. Naturally, the malaria parasite has several mecha-nisms by which it evades the immune system, even in the immunocompetent host, thereby creating a chronic infection. Despite several immune responses that do restrict parasite growth, the parasite persists. The different stages of the parasite express different antigens and many parasite proteins exhibit poly-morphism, e.g. there are about 50 different copies of the gene for the variable surface antigen PfEMP-1. During a chronic infection, the parasite is able to express different variant surface antigens, and thus allow multiplication of the parasite despite produc-tion of specific antibodies (Saul, 1999). In addition to the complex diversity of the parasite, the human host exhibits major heterogeneity in the immune response, depending on human leukocyte antigens (HLA) and other genetic as well as environmental factors.

The diversity of both the parasite and the immune response of the host may thus appear to be an unsur-mountable obstacle. There is, however, direct and indirect evidence for the potential success of a malar-ia vaccine. Immunization with eradiated sporozoites has provided protection in rodents, monkeys and


humans (Ritchie & Saul, 2002). Furthermore, peo-ple infected repeatedly with malaria will progres-sively develop naturally acquired immunity, which protects against clinical disease and also eventu-ally infection, although truly sterilizing immunity is difficult to achieve. In fact, the aim of a vaccine may not be to produce sterilizing immunity since its main objective is to prevent severe disease. It is also encouraging for vaccine development that in animal models both antisporozoite and anti-blood-stage vaccines have provided protection. In humans, trials for anti-sporozoite vaccines have shown protection with a recombinant vaccine based on the circum-sporozoite protein (Kester et al., 2001), in addition to previous and recent findings of protective immu-nity provided by eradiated sporozoites (Hoffman et al., 2002). Anti-blood-stage vaccines have up until now not shown any convincing effect (Alonso et al., 1994; Ritchie & Saul, 2002), whereas transmis-sion-blocking vaccines have provided evidence of efficacy, i.e. protecting feeding mosquitoes against infection by P. falciparum and P. vivax. (Carter et al., 2000; Hisaeda et al., 2000).

Certain principles can be identified regarding strate-gies for the development of vaccines. First, the anti-gens need to be accessible to the immune system and be limited in their antigenic diversity. Antigens need to be combined from different stages of the parasite and to include several antigens from each stage. At the same time, the vaccine should pref-erably not be too complex, and ensure the induc-tion of the right kind of immune responses. These principles are partly conflicting and compromises will be required (Ritchie & Saul, 2002). Specific adju-vant systems will be needed to drive the immune responses; these may include adjuvant formulations such as AS02 (Stoute et al., 1997; Bojang et al., 2001), or slow release and/or highly-immunogenic parti-cles (Birkett et al., 2002).

Several phase I and phase II vaccine trials have been conducted over the past 15 years. Most trials have tested vaccines directed against sporozoites and/or liver stages and have included different products, from synthetic peptide to recombinant malaria pro-teins, and even DNA-based vaccines. Different con-jugates and particle-forming constructs have been used. A common issue and problem has been insuf-ficiently strong and persistent immune response, even when the same vaccine candidate has caused a strong immune response in laboratory animals (Saul et al., 1999). Immune stimulatory conjugates or adju-vants have been tested and are still being developed for this purpose.

Only a few vaccine candidates have undergone

phase III and phase IV field trials. The principal vac-cine tested has been the synthetic peptide vaccine SPf66 (Patarroyo et al., 1988); after up to nine tri-als, a meta-analysis concluded that there was no evi-dence of efficacy in Africa, but there was possibly some effect in South America. Two other vaccine candidates that have been tested in clinical trials are the RTS, S vaccine and an asexual-stage cock-tail including one fragment of MSP-1, one form of MSP-2 and a portion of the ring-infected erythrocyte surface antigen (RESA). This vaccine, interestingly, provided some evidence of decrease in parasite den-sity in vaccinated individuals, but also a shift in the MSP-2 genotype of parasites (Genton et al., 2002), confirming the potential risk that a protective effect of a vaccine candidate may be only temporary and could be overcome by antigen shift in the parasite population.

Drugs

The targets of antimalarial drugs are those aspects of the metabolism of the parasite that are different from that of the human host. Drug targets have been haemoglobin degradation in the lysosomal food vac-uole (quinolines, artemisinins) (Francis et al., 1997; Eggleson et al., 1999; Pagola et al., 2000; Shenai et al., 2000; Coombs et al., 2001), and nucleotide biosyn-thesis and amino acid metabolism (antifolates).

In recent years, new developments in malaria che-motherapy have mainly been related to develop-ment of compounds in/from China (artemisinin derivatives, lumefantrine, piperaquine, pyronari-dine) and partly to new combinations of “old” drugs (atovaquone/proguanil, chlorproguanil/dapsone) (Winstanley, 2000). A few new promising deriva-tives from previously known groups of compounds have also emerged (e.g. etaquine).

With regard to future drug development, new tar-gets are also found in the haem degradation process, which involves many enzymes such as plasma-lepsins (Coombs et al., 2001) or aspartic proteases (Shenai et al., 2000) and several peptidases (Eggleson et al., 1999). The inhibition of these processes would prevent the effective degradation into haemozoin and result in accumulation of haem products that are toxic to the parasite. Resistance to the quinolines generally relates to decreased uptake of the drug into the vacuoles and thus this effect may potential-ly be reversed by other compounds such as vera-pamil, chlorpheniramine (Sowunmi et al., 1997), suggesting their potential to reverse resistance.

The new insights provided by the availability of the parasite genome have also identified lipid biosyn-


thesis genes in the apicoplast (Waller et al., 1998), the isoprienoid biosynthesis pathway and inhibitors thereof (Jomaa et al., 1999). Other identified drug targets are messenger RNA (mRNA) cap formation (Ho & Schuman, 2001), and the cystein and aspartyl classes of proteases that are important for digestion of haemoglobin (Francis et al., 1997; Gardner et al., 1998; Singh & Rosenthal, 2001). An example of the latter, which is not found in humans, and which is therefore of great interest is the metacaspase family of cystein proteases (Uren et al., 2000).

3.6 Social sciences

Understanding of care-seeking behaviour, beliefs and other social aspects related to malaria has increased substantially over the last two decades. The influences of social, cultural and economic fac-tors on treatment-seeking are being increasing-ly recognized, necessitating local context-specific approaches when designing malaria control strat-egies/activities (Agyepong et al., 1995). The full potential of social science still, however, remains to be realized (Williams et al., 2002). Social science com-prises many disciplines, namely anthropology, soci-ology, economics, political science, demography and communications, and each discipline is governed by its own theoretical framework.

Studies have developed a more in-depth under-standing of processes that determine knowledge, behaviour and attitudes. Examples are studies on mothers, on recognition of malaria-associated symptoms (Rooth & Björkman, 1992b; Mwenesi et al., 1995) and on the observation that convulsions (”degedege” in Swahili), are treated by traditional healers (Foster, 1995; Makemba et al., 1996), which may result in unnecessary deaths (Hausmann-Muela et al., 1998). Recent examples are studies on intra-household relations and treatment decision-making for childhood illness (Molyneux et al., 2002) and on how biomedical knowledge interacts and merges with local ideas and beliefs (Muela et al., 2002). The understanding of the degree and rea-sons for the use of the private health sector is also essential for optimal control of malaria (Kloos et al., 1987; Foster, 1995). Too many children still die even before attending health-care services (Deming et al., 1989). The importance of household-level eco-nomic impact is now increasingly acknowledged, e.g. for the optimal deployment of ITNs (Meltzer et al., 2003). In conclusion, community and household interventions can now be designed more frequently and better evaluated, as a result of improved under-standing of social processes (Marsh et al., 1999).

3.7 Malaria control interventions

Different specific intervention strategies have evolved in recent years. Some have been tested in a number of clinical trials, while the values of others need (urgently) to be explored and studied. The rec-ommended use of ITNs or insecticide-treated cur-tains is based on evidence from community-based studies (see 3.1). In contrast, there is already consen-sus that drug combination therapy needs to be pro-moted, although community-based studies are still required (see 3.4).

IPT is being advocated as a means to prevent mor-bidity and mortality in specific risk groups. During pregnancy, IPT has provided significant improve-ment in haemoglobin concentrations (Schulman et al., 1999), and recently three doses of sulfadoxine/pyrimethamine administered during infancy (IPTi) at the time of routine vaccinations was shown to reduce clinical malaria and the rate of severe anae-mia by about 50% (Schellenberg et al., 2001). While IPT in pregnancy (IPTp) is now being promoted as a general strategy to control malaria, the benefit of IPT in infancy (IPTi) requires further evaluation.

Home management has emerged as one major means to prevent severe manifestation and fatal outcome caused by late appearance at health-care facilities. This concept was strongly supported by data from a community-based study in Ethiopia (Kidane & Morrow, 2000). Local mother-coordina-tors were trained to teach mothers how to recog-nize the symptoms of malaria and to give prompt treatment to their children aged less than five years. This resulted in a 40% (95% CI, 29–51%) reduction of crude mortality in children aged less than five years. The use of rectal administration has emerged as another complementary option to prevent fatal outcome in the case of severe manifestations and/or difficulty with oral intake of standard treatment, at a household level. Artesunate, so far the only avail-able antimalarial for rectal application (rectocaps) is now being studied for its effectiveness at a few sites, after initial clinical trials demonstrated promising results with regard to efficacy and bio-availability.

Other intervention strategies are also being evalu-ated. These include both new concepts and more traditional tools, used under specific epidemiolog-ical conditions. Supplementation with iron part-ly prevented severe anaemia during infancy; this effect was reinforced by adding malaria chemopro-phylaxis (Menendez et al., 1997). The latter, how-ever, resulted in reduced acquisition of protective immunity, with an increase in the number of clin-ical malaria episodes after cessation of treatment.


In a more recent study, supplementation with zinc alone did not have any effect on morbidity attrib-utable to malaria in children aged less than three years (Müller et al., 2001). Combining ITNs and short-term mass treatment eliminated both vivax and falciparum malaria from an island in Vanuatu where malaria was endemic (Kaneko et al., 2000). The island remained free from malaria until seven years later, when ongoing surveillance revealed an epidemic of vivax malaria related to loss of protec-tive immunity in adolescents but not in adults.

An overall area that has received growing interest is the mapping and modeling of the geographical dis-tribution of malaria, as well as its ecological dynam-ics. New tools for such surveillance are remote sensing technologies, e.g. satellite sensors (Rogers et al., 2002). This provides potential for the devel-opment of early warning systems for epidemics, as well as predictors of mosquito distribution and transmission patterns and intensities.

4. CHALLENGES

4.1 Entomology

There is an overall consensus on the benefits of ITNs. However, wide-scale use of ITNs has not been successfully achieved. Finding the optimal means to promote deployment represents a challenge in terms of both operational research and equity. How can scaling-up be best achieved and what is the role of marketing? Under which circumstances should ITNs be provided at full cost, subsidized or free of charge? The issue of sustainability needs to be con-sidered. Is longer-lasting impregnation possible and essential?

A high ITN coverage in the community is neces-sary in order to achieve mosquito reduction (”mass effect”), including a significant decrease in transmis-sion in a highly endemic area. What is the coverage necessary for this effect? The cost–effectiveness of integrated vector control in various ecological cir-cumstances also needs to be addressed.

Generally, the value and possibly comparative advantage of IRS needs to be revisited. What is its role in comparison to or in combination with other new and evolving control strategies?

In order to prevent and/or reverse the development of resistance to insecticides, including pyrethroids, the diversity of the families of enzyme involved in resistance needs to be elucidated. This is also cru-cial to the development of future insecticides and improvements in their formulations, including

the potential for adding synergistic compounds. If inhibitors of resistance that are non-toxic to humans (i.e. insect-specific) can be developed, they will be marketed more rapidly than totally new insecticide compounds which will take a longer time to devel-op and at a higher cost.

The elucidation of new regulatory and metabolic pathways in mosquitoes will allow new target mol-ecules to be identified. A comparison with human genomics will identify processes that are unique to insects, thus preventing the risk of toxicity to humans.

Genetic interference with reproduction by means of a released insect population, represents a new and challenging alternative strategy for the reduc-tion of vector populations. It must, however, be realized that the effectiveness of this “sterile insect technique” is dependent on population structure and dynamics and is maybe unlikely to be effective in highly endemic areas of Africa. Specific genet-ic manipulation of vectorial capacity represents an additional potential means to more directly reduce malaria transmission.

With regard to genetically modified mosquitoes, general safety concerns have to be dealt with. The mode of introduction of the modified mosquitoes into the natural environment needs to be consid-ered. Population replacement may be one alterna-tive, i.e. by first eliminating the existing mosquito population with insecticides, leaving a biological niche for the new population. Use of transposable elements, as in Drosophila, or the introduction of symbionts, or the introduction of certain genes that drive meiosis are potential means to support the fit-ness of transformed mosquitoes. Clearly, an optimal understanding of mosquito population structures and local ecologies are crucial in this context. For example, a conceivable risk is that virulence intro-duced into transgenic mosquitoes may move over to the non-refractory mosquitoes. Obviously there are major political and ethical issues, including that of public perception, that need to be dealt with.

4.2 Pathogenesis and immunology

Understanding of the host–parasite interaction still needs to be significantly improved. Increasing knowledge of the molecular pathways that mediate these interactions is a prerequisite for this. Improved insight into parasite-induced immune responses is also the basis for optimal interventions, especially efforts to develop vaccines.

A better understanding of pathogenic mechanisms,


including immunopathological as well as patho-physiological features such as metabolic acidosis, is necessary for a possible improvement in treatment principles for severe malaria.

4.3 Clinical manifestations

Does chronic/recurrent malaria result in ill health? Does it predispose to other infections/diseases? Is the resulting anaemia associated with impaired cog-nitive functions and behaviour? Understanding of the effects of malaria on cognition and other cere-bral functions has improved recently, but is still too scanty to identify needs as well as tools/strategies for its prevention and treatment.

The challenges in relation to anaemia caused by malaria include improved understanding of the dynamics of the malaria infection, the immunolog-ical responses and the destruction and reduced pro-duction of erythrocytes. This is a prerequisite for optimal interventions strategies, i.e. how and when to prevent or treat anaemia. The criteria for life-sav-ing blood transfusion represents a special research challenge, especially in view of the need for more restricted indications, because of the risks of iatro-genic transmission of HIV.

Diagnostic tests, both microscopy and rapid tests, can contribute to improved and more cost-effective management of disease, and reduce the unnecessary and irrational use of antimalarial drugs. There is a need for evaluating the feasibility and efficiency of diagnostic tests at a peripheral level, and also a need for improved simple diagnostic tests.

Does malaria interact with other infections? How does malaria infection prevent or aggravate the man-ifestations of other concomitant infections? What are the implications for malaria of the immune stimula-tion or suppression caused by some infections and the switch between T-helper 1 and 2 (Th1 and Th2) immune responses observed in some infections?

4.4 Chemotherapy and drug resistance

Better use of existing drugs needs to be based on a better understanding of the dynamics of the evo-lution of drug resistance. What is the optimal type of surveillance for drug treatment policy decisions? Which methods should be used and what are the criteria for change in policy? What are the dynam-ics between exposure to a drug and development and selection of drug resistance in parasites in dif-ferent situations of malaria transmission? What are the respective roles of concentrations of (inhibito-ry) drug that are persistently above the minimum

inhibitory concentration (MIC) versus (parasiticid-al) high peak concentrations?

The above issues may be addressed in pharma-codynamic studies both in vitro and in vivo. The reasoning and theories have been developed, but experimental studies are still too scanty. The use of molecular markers offers new possibilities for such studies. Transfection technology will assist in the identification of molecules responsible for drug resistance and an improved understanding of the molecular dynamics and strategies that parasites use to survive exposure to a drug.

What is the role of combination therapy and what are the optimal partner drug combinations? What drug interactions may be anticipated in combination therapy? The optimal pharmacokinetic combina-tion of two compounds remains unsettled. Should the elimination kinetics of the partner drugs match or rather be rapid and slow, respectively? This may partly depend on the risk for development/selec-tion of resistance to a specific drug during the phar-macokinetic elimination phase, especially during high transmission, i.e. re-infection. Which is/are the optimal partner drug(s) to accompany artemisinin derivatives for African countries, considering that SP when used on its own already appears to have selected rather rapidly for drug resistance in some areas after its introduction on a large scale.

Presently, the pharmacological properties of antima-larial drugs are largely evaluated in adult men, non-pregnant women and children aged more than two years. All this is of concern in relation to the new chemotherapy policies, including new drug com-binations and IPT in infancy and pregnancy. The increasing understanding of diversity in pharmaco-genetics and thus also pharmacokinetic phenotypes between individuals as well as between populations also offers new scientific challenges in understand-ing possible differences in the inherent efficacy and tolerability of antimalarial drugs.

4.5 Vaccine and drug development

The potential of genomics and proteomics for the future identification of new drugs and vaccine tar-gets is obvious, but the new insights also confirm and reveal constraints often related to the wide potential for diversity of the falciparum parasite.

For drug development, new key targets that are now being considered include, for example, the api-coplast and the mitochondrion. Generally, the new genome insights and bioinformatics offer great opportunities for the identification of novel drug


targets. An overall challenge/problem for the devel-opment of new compounds is, however, the high costs involved and the current lack of market incen-tives for the pharmaceutical industry.

For vaccine development, some lead antigens of the malaria parasite are conserved while others are poly-morphic and even highly polymorphic. Overall, the more polymorphic antigens are also more immuno-genic and involved in more critical functions for the parasite. This obviously represents a major problem and challenge for the development of a highly effica-cious vaccine candidate. The obvious risk is that the better the effect the greater the tendency for a switch in parasite diversity towards a parasite population that is not susceptible to the immune response elic-ited by the vaccine candidate. An additional chal-lenge/focus for vaccine development is finding an optimal formulation and delivery, including poten-tial genetic vaccination.

From clinical requirement and public health fea-sibility perspectives, the overall challenges for a future vaccine, or vaccine “cocktail” are the fol-lowing characteristics: it needs to be safe, well tol-erated, affordable and with a dosing regimen, preferably compatible with the Expanded Program on Immmunization (EPI) scheme and it needs to be effective in small children from the age of 6 months and preferably in all age groups. A minimal effica-cy might be 50% protection against especially severe disease for at least one year, but higher protection for a longer duration would be preferable.

In relation to the evaluation of malaria vaccines in endemic areas, a major issue is the choice of end-points, especially in relation to vaccines that combat morbidity (disease). While reduction of death and severe malaria may be the main objective of the vac-cine, surrogate markers of such efficacy may have to be chosen, both for ethical reasons and because it may not be possible to carry out sufficiently large trials, at least in early trials to achieve statistical sig-nificance on parameters of severe disease. Anti-infection vaccines are simpler to test in this context, since the outcome is infection only upon challenge, but here efficacy may be harder to achieve. Finally, gametocyte (mosquito)-stage vaccines may also be straightforward to test since they are expected to block transmission of the parasites to mosquitoes. Eventual proof of concept will, however, need to be demonstrated in large community-based trials. A challenge in the evaluation of malaria vaccines is also the capacity for producing enough materi-al for protein-based vaccines to be tested in a suffi-ciently large number of volunteers. Field sites are at any rate being developed, including acquiring tech-

nical competence, for performing clinical trials from phase I to phase IV.

4.6 Social sciences

Well-trained social scientists have the opportunity to provide major research inputs if they are more closely integrated in malaria control activities and thus can better perceive and understand the needs, i.e. the key research questions. Be it anthropologists or health economists, social scientists could and should be more proactive in defining the research agenda and challenging existing methods of inter-vention.

One general research question for social scientists is how new biomedical tools are best integrated into malaria control strategies. Another research chal-lenge is health economics of the malaria burden, and the different control strategies. With increased rec-ognition of the malaria problem, including its social and economic implications, there is and will be an increasing need and demand for elaborate analyses of potential benefits of both research investments and resource allocation to control activities.

The current alarming situation of increasing resis-tance to commonly-used antimalarial drugs also represents a special challenge to social scientists, since this new situation necessitates a switch to more expensive and complex treatments, with asso-ciated problems of costs and compliance. Home-management/treatment of childhood fever needs to be generally addressed in a rigorous manner with a multidisciplinary approach. More challenges that require social science approaches lie ahead, with the upcoming diversity of specific control strate-gies that address different risk groups in the popula-tion. These include IPT in pregnancy and in infancy, ITNs, presumptive home treatment including rectal administration of “rectocaps” etc.

4.7 Malaria control interventions

The role of IPT in infancy needs to be evaluated in more depth. With regard to both IPTi and IPTp dif-ferent factors also need to be considered, such as transmission and selection of drug, be it mono- or combination therapy. In areas of higher transmis-sion, there is need for a longer suppressive effect by residual drug, i.e. a long drug elimination half-life. This, however, also increases the risk of selecting for drug resistance. Hence, more studies are needed, including data on prevention of mortality.

With regard to combination therapy, there is still lack of evidence on its perceived benefits and its fea-sibility when used on a larger scale in areas of high


endemicity. So far, community-based evidence for beneficial effects of combination therapy mainly relies on data from Thailand and only on the use of mefloquine as a partner drug to artemisinin deriva-tives.

Generally, these community-based intervention tri-als need to address not only effects on morbidity and mortality caused by malaria, but also to con-sider pharmacovigilance (after introduction of new therapies), health economics, social acceptability etc. Only then will the research provide good enough data for the policy-makers to develop, improve and implement optimal malaria control.

The efficiencies of different health system policies also need to be better addressed on a scientific basis. This may include the effects of training and rein-forcement of existing health-care facilities only, or the introduction of specific improvement, such as diagnostic tools, e.g. microscopy, better referral sys-tems etc.

5. OPPORTUNITIES/RECOMMENDATIONS

• To improve understanding of biological pro-cesses in mosquitoes, including development of resistance to insecticides.

• To identify new regulatory and metabolic path-ways and to compare mosquito and human genomics in order to identify new targets for insecticides that are insect-specific and thus without risk of toxicity to mammals/humans.

• To further elucidate vector capacity/refractori-ness, which may provide targets for gene modi-fication in mosquitoes.

• To improve understanding of the structure of wild mosquito populations and of how to introduce transgenes, and to deal with safety concerns.

• To investigate how best to prolong, monitor and protect the effectiveness of pyrethroids.

• To assess different models for scaling up use of ITNs and their sustainability. This involves financing, e.g. marketing vouchers or free access, as well as longer-lasting impregnation and re-impregnation.

• To revisit and study any comparative advantage of IRS under different epidemiological condi-tions.

• To continue to improve our understanding of genetic, molecular, immunological host–parasite interactions.

• To further investigate the pathogenesis and pathophysiology of cerebral malaria and other manifestations of acute severe malaria, in order to improve treatment.

• To pursue further studies on the pathogenesis, morbidity and mortality of P. falciparum-asso-ciated anaemia, including its prevention and treatment.

• To determine the immune responses that are critical for protective immunity, especially the relative role of immune responses to highly polymorphic antigens (e.g. PfEMP-1) compared with more conserved antigens.

• To further pursue the search for and assessment of vaccine candidates, including their formula-tions, while considering the different require-ments (e.g. need for longevity of the immune response) in different target populations, such as infants, pregnant women and migrants.

• To study the interactions between malaria and different infectious diseases (e.g. HIV), and the related immune responses.

• To accelerate the search for new potential drug targets and to provide incentives for the devel-opment of candidate antimalarial compounds.

• To provide community-based evidence for the rationale of combination therapy (“proof of drug combination principle”).

• To address the issue of potential pharmacologi-cal drug interactions with regard to antimalarial efficacy and host safety.

• To address the issue of compliance to different treatment regimens.

• To address the area of pharmacogenetics and population pharmacokinetics generally, as well as the pharmacological implications of the use of different drugs in special groups, such as infants and pregnant women.

• To develop scientifically sound pharmacovigi-lance, in view of the expected new policies for drug treatment in the near future.

• To better address scientifically the dynamics between drug use/exposure and emergence, evolution and spread of resistance, from molec-ular to epidemiological perspectives.

• To further study the benefits of IPT and the opti-mal choices of drugs or combinations thereof in IPTp as well as IPTi.

• To address “home management” from many perspectives, i.e. from choices of drugs under different drug resistance situations to the use of rectocaps and the feasibility of different diag-nostics and drug policies at home or close to home (village) level.

• To improve and/or develop new rapid diagnos-tic tests in order to improve characteristics such as specificity, ease of use and robustness.

• To perform multidisciplinary studies on com-munity interventions, in view of new and more targeted control strategies.

• To specifically develop and include health eco-


nomics in the evaluation of community inter-ventions, in order to develop a scientifically sound basis for setting priorities.

• To involve social scientists more proactively in defining the research agenda, especially with the introduction of new control strategies, but also with regard to the development of new potential tools resulting from advances in biomedicine.

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